{"gene":"SUN2","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":2004,"finding":"SUN2 is a mammalian inner nuclear membrane (INM) protein; its N-terminal region (amino acids 26–339) is sufficient for nuclear envelope localization, while its C-terminal SUN domain resides in the perinuclear lumen between the inner and outer nuclear membranes.","method":"Immunofluorescence, subcellular fractionation, EM, recombinant GFP/V5-tagged protein expression in HeLa cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (IF, EM, biochemical fractionation, truncation mapping) in a single study","pmids":["15082709"],"is_preprint":false},{"year":2007,"finding":"SUN2 specifically localizes to meiotic telomere attachment sites at the nuclear envelope and is part of a membrane-spanning fibrillar complex that interconnects telomeres with cytoplasmic structures, functioning in meiotic telomere tethering and bouquet formation.","method":"Immunolocalization, electron microscopy, co-localization analysis in mouse spermatocytes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal IF and EM with functional context, replicated conceptually in multiple organisms","pmids":["17452644"],"is_preprint":false},{"year":2009,"finding":"SUN1 and SUN2 act together at the nuclear envelope to retain Syne-1/Nesprin-1 at the nuclear envelope of muscle cells; loss of both proteins (Sun1/2 double-knockout) displaces Syne-1 from the NE and disrupts both synaptic and non-synaptic myonuclear positioning in skeletal muscle.","method":"Genetic knockout (Sun1-/-, Sun2-/-, double-KO mice), immunofluorescence, histology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean mouse genetic epistasis with specific cellular phenotype, gene-dosage effect demonstrated","pmids":["19509342"],"is_preprint":false},{"year":2010,"finding":"INM targeting of SUN2 requires three distinct elements: a classical nuclear localization signal (cNLS) in the nucleoplasmic N-terminal domain, a cluster of arginines that mediates Golgi retrieval via coatomer, and the C-terminal lumenal SUN domain.","method":"Deletion/mutation analysis, fluorescence microscopy, Golgi retrieval assays in human cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — systematic domain mutagenesis with functional localization readouts, multiple orthogonal methods","pmids":["20551905"],"is_preprint":false},{"year":2011,"finding":"Lamin A (but not lamin C) is required to maintain SUN2 at the nuclear envelope; Rab5 overexpression redistributes SUN2 to endosomes via its SUN domain, and SUN2 participates in endocytosis, as its overexpression stimulates transferrin uptake while knockdown attenuates it.","method":"siRNA knockdown, overexpression of Rab5 mutants, co-localization, transferrin uptake assay in HeLa and lamin A/C-deficient cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple assays but mechanistic link is correlative for endocytosis role","pmids":["21655223"],"is_preprint":false},{"year":2012,"finding":"SUN1 and SUN2 interact with the DNA-PK complex (which functions in non-homologous end joining) and are required for proper activation of ATM and H2AX after DNA damage; Sun1/Sun2 double-KO MEFs show premature proliferation arrest, increased apoptosis, DNA damage, and impaired DDR signaling.","method":"Biochemical co-immunoprecipitation screen, Sun1/2 double-KO MEFs, flow cytometry, immunofluorescence for γH2AX and pATM","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with multiple orthogonal readouts plus biochemical interaction screen","pmids":["22863315"],"is_preprint":false},{"year":2012,"finding":"In mandibuloacral dysplasia (MADA) cells, farnesylated prelamin A accumulation alters SUN2 distribution at the nuclear envelope (forming a disorganized lattice); statin treatment partially rescues proper SUN2 organization, indicating SUN2 localization depends on prelamin A farnesylation status.","method":"Immunofluorescence, pharmacological treatment (farnesyltransferase inhibitors, statins) in MADA patient fibroblasts","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, pharmacological rescue with IF readout","pmids":["22706480"],"is_preprint":false},{"year":2014,"finding":"Disease-associated SUN1 and SUN2 variants impair rearward nuclear repositioning in fibroblasts (defective nuclear-cytoskeletal coupling), and patient myotubes with compound heterozygous SUN1 mutations show loss of pericentrin recruitment to the NE, impaired microtubule nucleation at the NE, and defective myonuclear positioning.","method":"Nuclear repositioning assay in fibroblasts, immunofluorescence in patient myotubes and C2C12 myotubes expressing SUN variants","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — patient-derived cells plus exogenous mutant expression, multiple orthogonal phenotypic readouts","pmids":["25210889"],"is_preprint":false},{"year":2016,"finding":"SUN2 overexpression blocks HIV-1 infection between reverse transcription and nuclear import in a capsid-dependent, cyclophilin A (CypA)-dependent manner; this block and the accompanying nuclear shape deformation both map to the nucleoplasmic domain of SUN2 that interacts with the nuclear lamina. Passaging selected a single CA mutation conferring SUN2 resistance.","method":"Overexpression, siRNA knockdown, CypA inhibition, chimeric virus analysis, capsid passaging in cell lines and primary monocyte-derived dendritic cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (domain mapping, CypA perturbation, viral passaging) in single study","pmids":["26865710"],"is_preprint":false},{"year":2016,"finding":"Endogenous SUN2 in primary CD4+ T cells is required for the positive effects of CypA on HIV reverse transcription and nuclear import; SUN2 and CypA act in the same pathway to promote wild-type HIV infection, whereas capsid mutants restricted by CypA are blocked at nuclear import in a SUN2-dependent manner.","method":"siRNA knockdown of SUN2, CypA inhibition/knockdown, infection assays with HIV-1, HIV-2, SIVmac capsid mutants in primary CD4+ T cells","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple viral strains and orthogonal perturbations in primary cells","pmids":["27149839"],"is_preprint":false},{"year":2017,"finding":"SUN2 silencing in primary CD4+ T cells reduces HIV infection indirectly by impairing T cell activation and proliferation (reduced activation markers, viability, and viral protein expression), rather than through a direct CypA-dependent antiviral mechanism.","method":"siRNA knockdown, flow cytometry for activation markers, proliferation and viability assays, infection assays in primary CD4+ T cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — orthogonal functional assays (activation, proliferation, viability, infection) in primary cells","pmids":["28077629"],"is_preprint":false},{"year":2017,"finding":"SUN1 and SUN2 overexpression inhibit nuclear import of HIV-1 cDNA; in vitro-assembled HIV-1 capsid-nucleocapsid nanotubes capture SUN1 and SUN2 from cell lysates, indicating direct interaction with the viral capsid. CRISPR/Cas9 knockout of SUN2 modestly reduces HIV-1 infectivity.","method":"Overexpression screen, CRISPR/Cas9 knockout, capsid-nucleocapsid nanotube pulldown from cell lysates, infection assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro capsid binding assay plus genetic KO with functional readout","pmids":["28747499"],"is_preprint":false},{"year":2018,"finding":"SUN2 associates with lamin A/C to tether repressive nucleosomes 1 and 2 at the HIV-1 5'-LTR, blocking RNA polymerase II recruitment; SUN2 knockdown converts this chromatin to an active state, enhancing RNA Pol II phosphorylation and recruitment to the LTR, leading to HIV-1 reactivation from latency.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, TNF-α reactivation assay in HIV-latently infected cell lines","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — ChIP and Co-IP with functional viral reactivation readout, multiple orthogonal methods","pmids":["29717016"],"is_preprint":false},{"year":2018,"finding":"Full-length SUN2 must transition from an autoinhibited monomer to a trimer (mediated by coiled-coil domains CC1 and CC2 preceding the SUN domain) to bind KASH; MD simulations and gel filtration identify residue E452 on CC1 as important for monomer-trimer transition, and Ca2+ can drive this transition.","method":"Molecular dynamics simulation (~1 µs), gel filtration chromatography, mutagenesis of E452","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 1 for computational + biochemical, but no structural validation; single lab","pmids":["29995584"],"is_preprint":false},{"year":2019,"finding":"SUN2-null mice develop cardiac hypertrophy with enhanced AKT/MAPK signaling but without fibrosis; in the absence of SUN2, levels of MAN1 (a negative regulator of TGFβ signaling) are elevated at the nuclear envelope, uncoupling hypertrophy from profibrotic TGFβ signaling.","method":"SUN2 knockout mouse model, cardiac histology, western blot for AKT/MAPK/TGFβ pathway components and MAN1","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined molecular pathway (MAN1/TGFβ), multiple orthogonal readouts","pmids":["31091167"],"is_preprint":false},{"year":2021,"finding":"SUN2 is a component of a spliceosome complex; pulldown followed by mass spectrometry identified SUN2 as interacting with splicing factors SNRPD2, SNRPD3, and NHP2L1, and SUN2 is required for efficient sororin pre-mRNA splicing, thereby regulating sister chromatid cohesion and cell proliferation.","method":"RNAi screen, pulldown/mass spectrometry, RT-PCR for sororin intron retention, FACS, molecular imaging in TNBC cell lines","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 — pulldown/MS plus functional splicing assay, but single lab","pmids":["33648524"],"is_preprint":false},{"year":2022,"finding":"Casein Kinase 2 phosphorylates SUN2, enabling its binding to the SCFβTrCP ubiquitin ligase; SCFβTrCP ubiquitinates SUN2, which is then extracted from the membrane by p97 AAA ATPase and degraded by the proteasome. CTDNEP1 phosphatase opposes CK2 to stabilize SUN2. Non-degradable SUN2 accumulation causes aberrant nuclear architecture, DNA damage vulnerability, and increased lagging chromosomes.","method":"Co-immunoprecipitation, ubiquitination assays, phosphorylation assays, p97 inhibition, proteasome inhibition, CRISPR/siRNA knockdown, live-cell imaging, chromosome segregation analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — reconstituted ubiquitination pathway with multiple orthogonal methods and functional phenotypic readouts, single rigorous paper","pmids":["36318477"],"is_preprint":false},{"year":2022,"finding":"SUN2 is required for HSV-1 restriction: disruption of SUN2 (by dominant-negative constructs or RNAi) increases extracellular HSV-1 viral yields, and SUN2 has greater impact on perinuclear spacing in infected cells than SUN1, suggesting SUN2 restricts HSV-1 egress by regulating perinuclear space width.","method":"Dominant-negative SUN constructs, RNAi knockdown, viral yield assays, electron microscopy for perinuclear spacing","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic perturbation plus EM structural readout, single lab","pmids":["35435724"],"is_preprint":false},{"year":2022,"finding":"ECM rigidity upregulates SUN2 expression, which promotes metaphase-to-anaphase transition by organizing astral microtubules during mitosis; on soft ECM, low SUN2 levels perturb astral microtubule organization and delay anaphase onset.","method":"Polyacrylamide gels of varying stiffness, SUN2 knockdown/overexpression, live-cell imaging of mitosis, immunofluorescence of mitotic spindle","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — mechanistic link between ECM rigidity, SUN2 expression, and spindle organization demonstrated with loss- and gain-of-function plus live imaging","pmids":["36322767"],"is_preprint":false},{"year":2023,"finding":"Conserved cysteine residues in SUN2 undergo KASH-dependent inter- and intra-molecular disulfide bond rearrangements in the ER lumen; disruption of the terminal SUN2 disulfide bond impairs SUN2 localization, turnover, LINC complex assembly, cytoskeletal organization, and cell migration. ER lumenal components regulate SUN2 cysteine redox state.","method":"Conformation-specific antibody, biochemical disulfide trapping, KASH co-expression experiments, pharmacological and genetic ER redox perturbations, cell migration assays","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical disulfide mapping, conformation-specific antibody tool, and functional migration readout; multiple orthogonal methods","pmids":["37188462"],"is_preprint":false},{"year":2023,"finding":"Progerin aggregation at the nuclear envelope triggers ER stress in HGPS in a SUN2-dependent manner; SUN2 clustering in the nuclear membrane is required for ER stress induction, suggesting SUN2 acts as a sensor that signals nuclear protein aggregates to the ER lumen.","method":"siRNA knockdown of SUN2, ER stress reporters, immunofluorescence of SUN2 clustering in HGPS cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined ER stress readout, but mechanism of luminal signaling not fully reconstituted","pmids":["37210724"],"is_preprint":false},{"year":2023,"finding":"Sun2 suppression reduces nuclear stiffness by increasing nuclear decoupling and deformability, thereby diminishing mechanical stress-induced nuclear/DNA damage in mesenchymal stromal cells; elevated Sun2 promotes RhoA activation and F-actin polymerization leading to nuclear stiffening.","method":"siRNA knockdown of Sun2 in WT and HGPS-model MSCs, cyclic mechanical stretch, nuclear deformability assays, RhoA/F-actin quantification, γH2AX measurement","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with biophysical nuclear mechanics readout and mechanistic pathway (RhoA/actin), single lab","pmids":["37198162"],"is_preprint":false},{"year":2024,"finding":"SUN2 promotes flavivirus (ZIKV, DENV, JEV) replication by facilitating cytoskeleton rearrangement and replication organelle formation; SUN2 is required for interaction between actin and ZIKV NS1, and dominant-negative Nesprin-1/2 (which link SUN2 to the cytoskeleton) reduces this actin–NS1 interaction and viral replication.","method":"CRISPR/Cas9 SUN2 knockout, dominant-negative Nesprin expression, co-immunoprecipitation (actin–NS1 interaction), viral RNA synthesis assay, neonatal mouse ZIKV infection model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO plus pulldown plus in vivo infection model, multiple orthogonal methods","pmids":["38177122"],"is_preprint":false},{"year":2024,"finding":"Calcium elevations trigger rapid nuclear actin assembly requiring SUN2 independently of its LINC complex function; SUN2 co-localizes and associates with the formin INF2 at the nuclear envelope in a calcium-regulated manner, and SUN2 is required for active RNA Pol II clustering in response to calcium elevations.","method":"siRNA knockdown, live-cell imaging of nuclear actin, co-immunoprecipitation of SUN2 with INF2, RNA Pol II clustering assay, calcium manipulation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function, co-IP, and functional gene expression readout with multiple orthogonal methods","pmids":["39317734"],"is_preprint":false},{"year":2026,"finding":"Paclitaxel induces nuclear aberrations in interphase through SUN2-dependent disruption of lamin A/C; paclitaxel treatment causes aberrant microtubule-vimentin bundle formation, and SUN2 mediates lamin A/C reduction through polyubiquitylation. Lamin A/C levels in turn determine cell survival and recovery after drug treatment.","method":"Advanced optical imaging, electron cryo-tomography, SUN2 knockdown/knockout, ubiquitylation assays, lamin A/C quantification, cell survival assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — cryo-ET plus biochemical ubiquitylation plus genetic perturbation with multiple functional readouts","pmids":["41367359"],"is_preprint":false},{"year":2026,"finding":"Sun2 is required for stiffness-dependent upregulation of extracellular matrix genes during lung fibrosis; Sun2-null fibroblasts can still become contractile myofibroblasts in response to TGFβ but fail to upregulate ECM protein-encoding genes, preventing fibrosis development in bleomycin-treated mice.","method":"Sun2-null mice, bleomycin lung fibrosis model, primary fibroblast substrate stiffness assays, gene expression analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO mouse with specific molecular/transcriptional readout, preprint","pmids":["41889916"],"is_preprint":true},{"year":2026,"finding":"SUN2 mediates stiffness-dependent chromatin regulation during skin fibrosis: on stiff substrates, SUN2 is required for changes in nuclear size, three distinct mechanosensitive chromatin states, and mechanical induction of the histone methyltransferase EZH2; loss of Sun2 abolishes stiffness-induced fibrotic gene expression and protects against bleomycin-induced skin fibrosis.","method":"Sun2 knockout, bleomycin skin fibrosis model, substrate stiffness experiments, chromatin state analysis, EZH2 assays in dermal fibroblasts","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model plus chromatin mechanistic readout, but preprint","pmids":["41890082"],"is_preprint":true},{"year":2026,"finding":"Farnesylated prelamin A inhibits nesprin-2/SUN2 LINC complex function by reducing the diffusional mobility of nesprin-2 and SUN2, thereby impairing actin-force transmission to the nucleus and causing cell polarity defects; this effect depends on the farnesyl moiety in the prelamin A tail.","method":"FRAP for diffusional mobility, nuclear repositioning/polarity assays, expression of tail fragments and farnesylation mutants in fibroblasts","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — FRAP plus functional polarity assays with mutagenesis of farnesylation site, multiple orthogonal approaches","pmids":["42011117"],"is_preprint":false}],"current_model":"SUN2 is an inner nuclear membrane protein whose SUN domain resides in the perinuclear lumen where it forms Ca2+/disulfide-regulated trimers to interact with KASH-domain nesprins, physically linking the nucleoskeleton to the cytoskeleton (LINC complex); it is targeted to the INM via a classical NLS, a Golgi retrieval signal, and its lumenal SUN domain, and its levels are controlled by CK2/CTDNEP1-regulated SCFβTrCP-mediated ubiquitination and p97-dependent membrane extraction. Through these structural and regulatory roles, SUN2 mediates myonuclear positioning, meiotic telomere tethering, DNA damage response (via interaction with DNA-PK), mechanotransduction (transmitting ECM stiffness signals to regulate mitotic spindle formation, chromatin state via EZH2, and ECM gene expression in fibrosis), nuclear actin polymerization via association with the formin INF2 in response to calcium, TGFβ/MAN1 signaling at the nuclear lamina, and early steps of HIV and flavivirus replication."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that SUN2 is an inner nuclear membrane protein with its SUN domain in the perinuclear lumen resolved the basic topology and subcellular localization of this previously uncharacterized protein.","evidence":"Immunofluorescence, EM, subcellular fractionation, and GFP-tagged truncation mapping in HeLa cells","pmids":["15082709"],"confidence":"High","gaps":["No binding partners identified","Functional role unknown","Mechanism of INM retention not defined"]},{"year":2007,"claim":"Demonstrating SUN2 localization at meiotic telomere attachment sites established its first specialized biological function — tethering telomeres to the nuclear envelope during meiosis for bouquet formation.","evidence":"Immunolocalization and EM in mouse spermatocytes","pmids":["17452644"],"confidence":"High","gaps":["Loss-of-function meiotic phenotype not yet shown","Mechanism of telomere recognition not defined"]},{"year":2009,"claim":"Genetic epistasis in Sun1/Sun2 double-knockout mice revealed that SUN proteins are collectively required to retain Nesprin-1 at the nuclear envelope and position myonuclei, establishing the LINC complex as essential for nuclear-cytoskeletal coupling in muscle.","evidence":"Sun1⁻/⁻, Sun2⁻/⁻, and double-KO mice with histology and IF","pmids":["19509342"],"confidence":"High","gaps":["Individual contribution of SUN2 vs SUN1 not fully separated","Molecular basis of force transmission not resolved"]},{"year":2010,"claim":"Systematic mutagenesis revealed that INM targeting of SUN2 requires three cooperating signals — a classical NLS, an arginine-based Golgi retrieval motif, and the lumenal SUN domain — explaining how the protein navigates the secretory pathway to reach the inner nuclear membrane.","evidence":"Deletion/mutation analysis with fluorescence localization in human cells","pmids":["20551905"],"confidence":"High","gaps":["Identity of Golgi retrieval receptor/coatomer interaction not fully characterized","Kinetics of INM targeting not measured"]},{"year":2012,"claim":"Two concurrent advances linked SUN2 to genome integrity: interaction with DNA-PK and a requirement for ATM/γH2AX activation in double-KO MEFs established SUN proteins as components of the DNA damage response, while studies in laminopathy cells showed SUN2 organization depends on prelamin A farnesylation status.","evidence":"Co-IP screen, Sun1/2 double-KO MEFs with DDR readouts; IF and pharmacological rescue in MADA patient fibroblasts","pmids":["22863315","22706480"],"confidence":"High","gaps":["Whether SUN2 directly contacts DNA-PK or acts through lamin scaffolding unknown","Mechanism by which prelamin A farnesylation disrupts SUN2 lattice not defined at structural level"]},{"year":2014,"claim":"Disease-associated SUN1/SUN2 variants impaired nuclear repositioning and microtubule nucleation at the nuclear envelope, providing the first human-genetics evidence that LINC complex dysfunction contributes to muscle disease pathogenesis.","evidence":"Nuclear repositioning assays in patient fibroblasts and myotubes expressing SUN variants","pmids":["25210889"],"confidence":"High","gaps":["Precise structural basis of variant pathogenicity not resolved","Whether SUN2 variants alone are sufficient to cause disease unclear"]},{"year":2016,"claim":"Multiple studies converged on a role for SUN2 in early HIV-1 infection, showing that overexpressed SUN2 blocks HIV nuclear import in a capsid- and CypA-dependent manner, while endogenous SUN2 in primary T cells supports wild-type HIV reverse transcription and nuclear entry.","evidence":"Overexpression/knockdown, CypA perturbation, viral passaging, infection assays in cell lines and primary CD4⁺ T cells","pmids":["26865710","27149839"],"confidence":"High","gaps":["Contradictory gain-of-function vs loss-of-function outcomes not fully reconciled","Direct physical interaction with capsid in cells not demonstrated"]},{"year":2017,"claim":"Further work clarified that SUN2 silencing in primary T cells reduces HIV infection indirectly by impairing T cell activation and proliferation, while in vitro capsid-nanotube pulldowns confirmed a direct SUN2-capsid physical interaction, partially resolving the apparent contradictions.","evidence":"siRNA knockdown with activation/proliferation assays in primary T cells; capsid-nucleocapsid nanotube pulldown plus CRISPR KO","pmids":["28077629","28747499"],"confidence":"High","gaps":["Whether the capsid interaction is physiologically relevant during natural infection remains debated","In vivo HIV infection in SUN2 KO model not tested"]},{"year":2018,"claim":"ChIP experiments revealed that SUN2, together with lamin A/C, tethers repressive nucleosomes at the HIV-1 5ʹ-LTR to maintain proviral latency, establishing a chromatin-level mechanism for SUN2's impact on HIV gene expression distinct from its nuclear import role.","evidence":"Co-IP, ChIP, siRNA knockdown with TNF-α reactivation in latently infected cell lines","pmids":["29717016"],"confidence":"High","gaps":["Whether this latency mechanism operates in primary reservoir cells in vivo unknown","How SUN2 is recruited specifically to the LTR not defined"]},{"year":2018,"claim":"Biochemical and computational analysis showed that full-length SUN2 exists as an autoinhibited monomer that undergoes Ca²⁺-driven trimerization via coiled-coil domains CC1/CC2, a prerequisite for KASH engagement — revealing an activation switch for LINC complex assembly.","evidence":"Molecular dynamics simulation, gel filtration, E452 mutagenesis","pmids":["29995584"],"confidence":"Medium","gaps":["No crystal structure of full-length SUN2 trimer","In vivo Ca²⁺ regulation of trimerization not demonstrated","Autoinhibition mechanism not validated by structural biology"]},{"year":2019,"claim":"SUN2-null mice developed cardiac hypertrophy with enhanced AKT/MAPK signaling but without fibrosis due to elevated MAN1 that suppresses TGFβ, demonstrating that SUN2 modulates the coupling between hypertrophic and fibrotic signaling at the nuclear lamina.","evidence":"SUN2 KO mice with cardiac histology, western blots for AKT/MAPK/TGFβ/MAN1","pmids":["31091167"],"confidence":"High","gaps":["Whether SUN2 directly regulates MAN1 levels or indirectly through NE reorganization is unknown","Heart-specific conditional KO not performed"]},{"year":2021,"claim":"Mass spectrometry identified SUN2 as an interactor of spliceosome components (SNRPD2, SNRPD3, NHP2L1), and SUN2 depletion caused sororin intron retention, linking SUN2 to pre-mRNA splicing regulation and consequently to sister chromatid cohesion.","evidence":"Pulldown/MS, RT-PCR for splicing, FACS in TNBC cell lines","pmids":["33648524"],"confidence":"Medium","gaps":["Whether SUN2 is a stable spliceosome component or an indirect regulator unclear","Not replicated in non-cancer cell types","Mechanism of SUN2 action on splicing not reconstituted"]},{"year":2022,"claim":"A complete degradation pathway was reconstituted: CK2 phosphorylates SUN2 to create a degron recognized by SCFβTrCP, leading to ubiquitination and p97-dependent membrane extraction for proteasomal degradation, with CTDNEP1 opposing CK2 — establishing how SUN2 abundance is dynamically controlled and why its dysregulation causes nuclear architecture defects and chromosome missegregation.","evidence":"Co-IP, in vivo/in vitro ubiquitination, phosphorylation assays, p97/proteasome inhibition, CRISPR/siRNA, live-cell imaging of chromosome segregation","pmids":["36318477"],"confidence":"High","gaps":["Cell-cycle timing of CK2/CTDNEP1 regulation not mapped","Whether this pathway is tissue-specific is unknown"]},{"year":2022,"claim":"Two parallel discoveries linked SUN2 to mechanotransduction and viral defense: ECM stiffness upregulates SUN2 to organize astral microtubules during mitosis, and SUN2 restricts HSV-1 egress by maintaining perinuclear space width.","evidence":"Variable-stiffness gels with live mitotic imaging and SUN2 perturbation; dominant-negative constructs and RNAi with HSV-1 yield and EM of perinuclear spacing","pmids":["36322767","35435724"],"confidence":"High","gaps":["How ECM stiffness transcriptionally upregulates SUN2 is not defined","Whether SUN2's perinuclear spacing role is relevant for HSV-1 in vivo unknown"]},{"year":2023,"claim":"Multiple 2023 studies revealed that SUN2 functions as a biophysical sensor: its lumenal disulfide bonds undergo KASH-dependent redox rearrangements essential for LINC assembly and cell migration; SUN2 clustering transduces progerin aggregation into ER stress in HGPS; and SUN2 levels regulate nuclear stiffness and mechanically-induced DNA damage via RhoA/F-actin.","evidence":"Disulfide trapping and conformation-specific antibody with migration assays; siRNA of SUN2 with ER stress reporters in HGPS cells; siRNA with nuclear deformability/γH2AX in MSCs under cyclic stretch","pmids":["37188462","37210724","37198162"],"confidence":"High","gaps":["Identity of ER oxidoreductase controlling SUN2 redox state unknown","Mechanism of SUN2 clustering-to-ER stress signal transduction not reconstituted","Whether reducing SUN2 is therapeutically viable in HGPS untested"]},{"year":2024,"claim":"SUN2 was shown to promote flavivirus replication by facilitating cytoskeletal rearrangement and replication organelle formation through actin–NS1 interaction, and independently to mediate calcium-triggered nuclear actin polymerization via the formin INF2 — revealing LINC-independent nuclear functions.","evidence":"CRISPR KO with co-IP (actin–NS1) and in vivo ZIKV model; siRNA with live nuclear actin imaging, co-IP of SUN2–INF2, calcium manipulation","pmids":["38177122","39317734"],"confidence":"High","gaps":["How SUN2 recruits INF2 specifically at the nuclear envelope not structurally resolved","Whether SUN2–INF2 function is relevant for endogenous nuclear actin beyond calcium signaling unknown"]},{"year":2026,"claim":"Recent work expanded SUN2's mechanotransduction role to fibrosis and drug response: SUN2 mediates stiffness-dependent ECM gene induction and EZH2-regulated chromatin remodeling in fibrosis, transmits paclitaxel-induced microtubule forces to cause lamin A/C polyubiquitylation and nuclear damage, and farnesylated prelamin A impairs LINC complex function by reducing SUN2/nesprin-2 mobility.","evidence":"Sun2 KO mice in bleomycin lung and skin fibrosis models with chromatin/transcription analysis; cryo-ET plus ubiquitylation assays with SUN2 KO in paclitaxel-treated cells; FRAP and polarity assays with farnesylation mutants","pmids":["41890082","41889916","41367359","42011117"],"confidence":"High","gaps":["Whether SUN2-dependent fibrotic mechanism is shared across all organ fibroses unknown","The ubiquitin ligase mediating SUN2-dependent lamin A/C degradation during paclitaxel treatment not identified","Therapeutic potential of targeting SUN2 in fibrosis or chemoresistance untested"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of full-length SUN2 autoinhibition and trimerization, how ECM stiffness signals are transduced to SUN2 transcriptional upregulation, the identity of ER oxidoreductases controlling SUN2 disulfide switches, and whether tissue-specific SUN2 functions can be therapeutically targeted in fibrosis, laminopathies, or viral infection.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length SUN2 structure available","Upstream mechanotransduction pathway to SUN2 expression undefined","In vivo therapeutic targeting not explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,13,19]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,18,21,22]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[18,20,21,26]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,3,6,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,12,23]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[19,20]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[16,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,21,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[16]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[25,26]}],"complexes":["LINC complex"],"partners":["SYNE1","SYNE2","SUN1","LMNA","DNA-PKCS","INF2","BTRC","CSNK2A1"],"other_free_text":[]},"mechanistic_narrative":"SUN2 is an inner nuclear membrane protein that functions as a core structural component of the LINC complex, coupling the nucleoskeleton to the cytoskeleton to transduce mechanical and biochemical signals between the nucleus and the cell exterior. Its C-terminal SUN domain resides in the perinuclear lumen where it undergoes Ca²⁺- and disulfide-regulated trimerization to engage KASH-domain nesprins, while INM targeting requires a classical NLS, a Golgi-retrieval signal, and the SUN domain itself; protein levels are controlled by CK2/CTDNEP1-regulated SCFβTrCP ubiquitination followed by p97-dependent membrane extraction [PMID:15082709, PMID:20551905, PMID:29995584, PMID:37188462, PMID:36318477]. Through this nucleocytoskeletal linkage, SUN2 mediates myonuclear positioning, meiotic telomere tethering, DNA damage response signaling via interaction with DNA-PK, mechanotransduction of ECM stiffness to regulate mitotic spindle organization and chromatin state (including EZH2-dependent histone methylation), calcium-triggered nuclear actin polymerization via association with the formin INF2, and stiffness-dependent fibrotic gene expression [PMID:19509342, PMID:17452644, PMID:22863315, PMID:36322767, PMID:39317734, PMID:41890082]. SUN2 also participates in viral biology: it maintains HIV-1 latency by tethering repressive chromatin at the proviral LTR via lamin A/C, facilitates flavivirus replication organelle formation through cytoskeletal rearrangement, and restricts HSV-1 egress by regulating perinuclear space width [PMID:29717016, PMID:38177122, PMID:35435724]."},"prefetch_data":{"uniprot":{"accession":"Q9UH99","full_name":"SUN domain-containing protein 2","aliases":["Protein unc-84 homolog B","Rab5-interacting protein","Rab5IP","Sad1/unc-84 protein-like 2"],"length_aa":717,"mass_kda":80.3,"function":"As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. Specifically, SYNE2 and SUN2 assemble in arrays of transmembrane actin-associated nuclear (TAN) lines which are bound to F-actin cables and couple the nucleus to retrograde actin flow during actin-dependent nuclear movement. Required for interkinetic nuclear migration (INM) and essential for nucleokinesis and centrosome-nucleus coupling during radial neuronal migration in the cerebral cortex and during glial migration. Required for nuclear migration in retinal photoreceptor progenitors implicating association with cytoplasmic dynein-dynactin and kinesin motor complexes, and probably B-type lamins; SUN1 and SUN2 seem to act redundantly. The SUN1/2:KASH5 LINC complex couples telomeres to microtubules during meiosis; SUN1 and SUN2 seem to act at least partial redundantly. Anchors chromosome movement in the prophase of meiosis and is involved in selective gene expression of coding and non-coding RNAs needed for gametogenesis. Required for telomere attachment to nuclear envelope and gametogenesis. May also function on endocytic vesicles as a receptor for RAB5-GDP and participate in the activation of RAB5","subcellular_location":"Nucleus inner membrane; Nucleus envelope; Endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9UH99/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SUN2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARL6IP6","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SUN2","total_profiled":1310},"omim":[{"mim_id":"618484","title":"ARTHROGRYPOSIS MULTIPLEX CONGENITA 3, MYOGENIC TYPE; AMC3","url":"https://www.omim.org/entry/618484"},{"mim_id":"617676","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 3; PSMD3","url":"https://www.omim.org/entry/617676"},{"mim_id":"615535","title":"SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 4; SYNE4","url":"https://www.omim.org/entry/615535"},{"mim_id":"614513","title":"TORSIN 1A-INTERACTING PROTEIN 2; TOR1AIP2","url":"https://www.omim.org/entry/614513"},{"mim_id":"613569","title":"SAD1 AND UNC84 DOMAIN-CONTAINING PROTEIN 2; SUN2","url":"https://www.omim.org/entry/613569"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SUN2"},"hgnc":{"alias_symbol":[],"prev_symbol":["UNC84B"]},"alphafold":{"accession":"Q9UH99","domains":[{"cath_id":"2.60.120.260","chopping":"547-714","consensus_level":"high","plddt":87.4141,"start":547,"end":714},{"cath_id":"1.20.5","chopping":"328-454","consensus_level":"medium","plddt":87.4125,"start":328,"end":454}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UH99","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UH99-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UH99-F1-predicted_aligned_error_v6.png","plddt_mean":67.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUN2","jax_strain_url":"https://www.jax.org/strain/search?query=SUN2"},"sequence":{"accession":"Q9UH99","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UH99.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UH99/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UH99"}},"corpus_meta":[{"pmid":"19509342","id":"PMC_19509342","title":"SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19509342","citation_count":197,"is_preprint":false},{"pmid":"15082709","id":"PMC_15082709","title":"Sun2 is a novel mammalian inner nuclear membrane protein.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15082709","citation_count":169,"is_preprint":false},{"pmid":"25210889","id":"PMC_25210889","title":"Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25210889","citation_count":138,"is_preprint":false},{"pmid":"17452644","id":"PMC_17452644","title":"Transmembrane protein Sun2 is involved in tethering mammalian meiotic telomeres to the nuclear envelope.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17452644","citation_count":134,"is_preprint":false},{"pmid":"26175118","id":"PMC_26175118","title":"Global loss of a nuclear lamina component, lamin A/C, and LINC complex components SUN1, SUN2, and nesprin-2 in breast cancer.","date":"2015","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26175118","citation_count":121,"is_preprint":false},{"pmid":"22863315","id":"PMC_22863315","title":"Inner nuclear envelope proteins SUN1 and SUN2 play a prominent role in the DNA damage response.","date":"2012","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/22863315","citation_count":90,"is_preprint":false},{"pmid":"25412930","id":"PMC_25412930","title":"Absence of SUN1 and SUN2 proteins in Arabidopsis thaliana leads to a delay in meiotic progression and defects in synapsis and recombination.","date":"2015","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25412930","citation_count":85,"is_preprint":false},{"pmid":"20551905","id":"PMC_20551905","title":"A classical NLS and the SUN domain contribute to the targeting of SUN2 to the inner nuclear membrane.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20551905","citation_count":78,"is_preprint":false},{"pmid":"26658802","id":"PMC_26658802","title":"SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26658802","citation_count":78,"is_preprint":false},{"pmid":"30282980","id":"PMC_30282980","title":"Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30282980","citation_count":53,"is_preprint":false},{"pmid":"35525855","id":"PMC_35525855","title":"FBXO2 targets glycosylated SUN2 for ubiquitination and degradation to promote ovarian cancer development.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35525855","citation_count":44,"is_preprint":false},{"pmid":"27149839","id":"PMC_27149839","title":"Nuclear Envelope Protein SUN2 Promotes Cyclophilin-A-Dependent Steps of HIV Replication.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27149839","citation_count":42,"is_preprint":false},{"pmid":"26865710","id":"PMC_26865710","title":"SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV.","date":"2016","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26865710","citation_count":41,"is_preprint":false},{"pmid":"36318477","id":"PMC_36318477","title":"Regulated degradation of the inner nuclear membrane protein SUN2 maintains nuclear envelope architecture and function.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36318477","citation_count":34,"is_preprint":false},{"pmid":"33648524","id":"PMC_33648524","title":"Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33648524","citation_count":34,"is_preprint":false},{"pmid":"21655223","id":"PMC_21655223","title":"Subcellular localization of SUN2 is regulated by lamin A and Rab5.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21655223","citation_count":28,"is_preprint":false},{"pmid":"24832085","id":"PMC_24832085","title":"Downregulation of SUN2, a novel tumor suppressor, mediates miR-221/222-induced malignancy in central nervous system embryonal tumors.","date":"2014","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24832085","citation_count":27,"is_preprint":false},{"pmid":"29717016","id":"PMC_29717016","title":"SUN2 Modulates HIV-1 Infection and Latency through Association with Lamin A/C To Maintain the Repressive Chromatin.","date":"2018","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/29717016","citation_count":26,"is_preprint":false},{"pmid":"22706480","id":"PMC_22706480","title":"Altered chromatin organization and SUN2 localization in mandibuloacral dysplasia are rescued by drug treatment.","date":"2012","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22706480","citation_count":26,"is_preprint":false},{"pmid":"31091167","id":"PMC_31091167","title":"Ablation of SUN2-containing LINC complexes drives cardiac hypertrophy without interstitial fibrosis.","date":"2019","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/31091167","citation_count":24,"is_preprint":false},{"pmid":"28077629","id":"PMC_28077629","title":"SUN2 Silencing Impairs CD4 T Cell Proliferation and Alters Sensitivity to HIV-1 Infection Independently of Cyclophilin A.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/28077629","citation_count":22,"is_preprint":false},{"pmid":"37198162","id":"PMC_37198162","title":"Nuclear softening mediated by Sun2 suppression delays mechanical stress-induced cellular senescence.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37198162","citation_count":20,"is_preprint":false},{"pmid":"33931868","id":"PMC_33931868","title":"Downregulation of SUN2 promotes metastasis of colon cancer by activating BDNF/TrkB signalling by interacting with SIRT1.","date":"2021","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33931868","citation_count":19,"is_preprint":false},{"pmid":"28747499","id":"PMC_28747499","title":"Effects of Inner Nuclear Membrane Proteins SUN1/UNC-84A and SUN2/UNC-84B on the Early Steps of HIV-1 Infection.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/28747499","citation_count":18,"is_preprint":false},{"pmid":"29995584","id":"PMC_29995584","title":"A molecular model for LINC complex regulation: activation of SUN2 for KASH binding.","date":"2018","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/29995584","citation_count":18,"is_preprint":false},{"pmid":"29163775","id":"PMC_29163775","title":"Loss of Sun2 promotes the progression of prostate cancer by regulating fatty acid oxidation.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29163775","citation_count":17,"is_preprint":false},{"pmid":"30675193","id":"PMC_30675193","title":"SUN2: A potential therapeutic target in cancer.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30675193","citation_count":17,"is_preprint":false},{"pmid":"36322767","id":"PMC_36322767","title":"SUN2 regulates mitotic duration in response to extracellular matrix rigidity.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36322767","citation_count":17,"is_preprint":false},{"pmid":"38177122","id":"PMC_38177122","title":"Nuclear membrane protein SUN2 promotes replication of flaviviruses through modulating cytoskeleton reorganization mediated by NS1.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38177122","citation_count":16,"is_preprint":false},{"pmid":"37210724","id":"PMC_37210724","title":"Activation of endoplasmic reticulum stress in premature aging via the inner nuclear membrane protein SUN2.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37210724","citation_count":16,"is_preprint":false},{"pmid":"37188462","id":"PMC_37188462","title":"Disulfide bond in SUN2 regulates dynamic remodeling of LINC complexes at the nuclear envelope.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/37188462","citation_count":12,"is_preprint":false},{"pmid":"39317734","id":"PMC_39317734","title":"SUN2 mediates calcium-triggered nuclear actin polymerization to cluster active RNA polymerase II.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/39317734","citation_count":11,"is_preprint":false},{"pmid":"33384835","id":"PMC_33384835","title":"Elevated Sad1 and UNC84 Domain Containing 2 (SUN2) level inhibits cell growth and aerobic glycolysis in oral cancer through reducing the expressions of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA).","date":"2020","source":"Journal of dental sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33384835","citation_count":6,"is_preprint":false},{"pmid":"37421143","id":"PMC_37421143","title":"Physcomitrium patens SUN2 Mediates MTOC Association with the Nuclear Envelope and Facilitates Chromosome Alignment during Spindle Assembly.","date":"2023","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37421143","citation_count":5,"is_preprint":false},{"pmid":"35435724","id":"PMC_35435724","title":"SUN2 Modulates the Propagation of HSV-1.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/35435724","citation_count":5,"is_preprint":false},{"pmid":"39288611","id":"PMC_39288611","title":"Long non-coding RNA SUN2-AS1 acts as a negative regulator of ISGs transcription to promote flavivirus infection.","date":"2024","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/39288611","citation_count":1,"is_preprint":false},{"pmid":"41308440","id":"PMC_41308440","title":"SUN2 downregulation promotes breast cancer cell proliferation via NFATC4 upregulation.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41308440","citation_count":0,"is_preprint":false},{"pmid":"41367359","id":"PMC_41367359","title":"Paclitaxel compromises nuclear integrity in interphase through SUN2-mediated cytoskeletal coupling.","date":"2026","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/41367359","citation_count":0,"is_preprint":false},{"pmid":"41889916","id":"PMC_41889916","title":"Loss of Sun2 ablates nuclear mechanosensing-driven extracellular matrix production and mitigates lung fibrosis.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41889916","citation_count":0,"is_preprint":false},{"pmid":"41890082","id":"PMC_41890082","title":"SUN2 mediates epigenetic remodeling to drive mechanotransduction during skin fibrosis.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41890082","citation_count":0,"is_preprint":false},{"pmid":"42011117","id":"PMC_42011117","title":"Farnesylated prelamin A induces fibroblast polarity defects in premature aging disorders by inhibiting nesprin-2-SUN2 LINC complex function.","date":"2026","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/42011117","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.17.638756","title":"Dissecting Force Transmission across SUN Proteins Using Nuclear Tension Sensors","date":"2025-02-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.17.638756","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.15.633301","title":"Elevated SUN1 promotes aging-related polarity defects through mechanical coupling microtubules to the nuclear lamina","date":"2025-01-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.15.633301","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.03.686286","title":"Intrinsic mechanotransduction during apical constriction licenses lineage competence in pluripotent stem cells","date":"2025-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.03.686286","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21806,"output_tokens":6583,"usd":0.082082},"stage2":{"model":"claude-opus-4-6","input_tokens":10281,"output_tokens":4604,"usd":0.249757},"total_usd":0.331839,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"SUN2 is a mammalian inner nuclear membrane (INM) protein; its N-terminal region (amino acids 26–339) is sufficient for nuclear envelope localization, while its C-terminal SUN domain resides in the perinuclear lumen between the inner and outer nuclear membranes.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, EM, recombinant GFP/V5-tagged protein expression in HeLa cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (IF, EM, biochemical fractionation, truncation mapping) in a single study\",\n      \"pmids\": [\"15082709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SUN2 specifically localizes to meiotic telomere attachment sites at the nuclear envelope and is part of a membrane-spanning fibrillar complex that interconnects telomeres with cytoplasmic structures, functioning in meiotic telomere tethering and bouquet formation.\",\n      \"method\": \"Immunolocalization, electron microscopy, co-localization analysis in mouse spermatocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal IF and EM with functional context, replicated conceptually in multiple organisms\",\n      \"pmids\": [\"17452644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SUN1 and SUN2 act together at the nuclear envelope to retain Syne-1/Nesprin-1 at the nuclear envelope of muscle cells; loss of both proteins (Sun1/2 double-knockout) displaces Syne-1 from the NE and disrupts both synaptic and non-synaptic myonuclear positioning in skeletal muscle.\",\n      \"method\": \"Genetic knockout (Sun1-/-, Sun2-/-, double-KO mice), immunofluorescence, histology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean mouse genetic epistasis with specific cellular phenotype, gene-dosage effect demonstrated\",\n      \"pmids\": [\"19509342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"INM targeting of SUN2 requires three distinct elements: a classical nuclear localization signal (cNLS) in the nucleoplasmic N-terminal domain, a cluster of arginines that mediates Golgi retrieval via coatomer, and the C-terminal lumenal SUN domain.\",\n      \"method\": \"Deletion/mutation analysis, fluorescence microscopy, Golgi retrieval assays in human cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic domain mutagenesis with functional localization readouts, multiple orthogonal methods\",\n      \"pmids\": [\"20551905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Lamin A (but not lamin C) is required to maintain SUN2 at the nuclear envelope; Rab5 overexpression redistributes SUN2 to endosomes via its SUN domain, and SUN2 participates in endocytosis, as its overexpression stimulates transferrin uptake while knockdown attenuates it.\",\n      \"method\": \"siRNA knockdown, overexpression of Rab5 mutants, co-localization, transferrin uptake assay in HeLa and lamin A/C-deficient cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple assays but mechanistic link is correlative for endocytosis role\",\n      \"pmids\": [\"21655223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUN1 and SUN2 interact with the DNA-PK complex (which functions in non-homologous end joining) and are required for proper activation of ATM and H2AX after DNA damage; Sun1/Sun2 double-KO MEFs show premature proliferation arrest, increased apoptosis, DNA damage, and impaired DDR signaling.\",\n      \"method\": \"Biochemical co-immunoprecipitation screen, Sun1/2 double-KO MEFs, flow cytometry, immunofluorescence for γH2AX and pATM\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple orthogonal readouts plus biochemical interaction screen\",\n      \"pmids\": [\"22863315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In mandibuloacral dysplasia (MADA) cells, farnesylated prelamin A accumulation alters SUN2 distribution at the nuclear envelope (forming a disorganized lattice); statin treatment partially rescues proper SUN2 organization, indicating SUN2 localization depends on prelamin A farnesylation status.\",\n      \"method\": \"Immunofluorescence, pharmacological treatment (farnesyltransferase inhibitors, statins) in MADA patient fibroblasts\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pharmacological rescue with IF readout\",\n      \"pmids\": [\"22706480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Disease-associated SUN1 and SUN2 variants impair rearward nuclear repositioning in fibroblasts (defective nuclear-cytoskeletal coupling), and patient myotubes with compound heterozygous SUN1 mutations show loss of pericentrin recruitment to the NE, impaired microtubule nucleation at the NE, and defective myonuclear positioning.\",\n      \"method\": \"Nuclear repositioning assay in fibroblasts, immunofluorescence in patient myotubes and C2C12 myotubes expressing SUN variants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived cells plus exogenous mutant expression, multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"25210889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SUN2 overexpression blocks HIV-1 infection between reverse transcription and nuclear import in a capsid-dependent, cyclophilin A (CypA)-dependent manner; this block and the accompanying nuclear shape deformation both map to the nucleoplasmic domain of SUN2 that interacts with the nuclear lamina. Passaging selected a single CA mutation conferring SUN2 resistance.\",\n      \"method\": \"Overexpression, siRNA knockdown, CypA inhibition, chimeric virus analysis, capsid passaging in cell lines and primary monocyte-derived dendritic cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (domain mapping, CypA perturbation, viral passaging) in single study\",\n      \"pmids\": [\"26865710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Endogenous SUN2 in primary CD4+ T cells is required for the positive effects of CypA on HIV reverse transcription and nuclear import; SUN2 and CypA act in the same pathway to promote wild-type HIV infection, whereas capsid mutants restricted by CypA are blocked at nuclear import in a SUN2-dependent manner.\",\n      \"method\": \"siRNA knockdown of SUN2, CypA inhibition/knockdown, infection assays with HIV-1, HIV-2, SIVmac capsid mutants in primary CD4+ T cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple viral strains and orthogonal perturbations in primary cells\",\n      \"pmids\": [\"27149839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SUN2 silencing in primary CD4+ T cells reduces HIV infection indirectly by impairing T cell activation and proliferation (reduced activation markers, viability, and viral protein expression), rather than through a direct CypA-dependent antiviral mechanism.\",\n      \"method\": \"siRNA knockdown, flow cytometry for activation markers, proliferation and viability assays, infection assays in primary CD4+ T cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal functional assays (activation, proliferation, viability, infection) in primary cells\",\n      \"pmids\": [\"28077629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SUN1 and SUN2 overexpression inhibit nuclear import of HIV-1 cDNA; in vitro-assembled HIV-1 capsid-nucleocapsid nanotubes capture SUN1 and SUN2 from cell lysates, indicating direct interaction with the viral capsid. CRISPR/Cas9 knockout of SUN2 modestly reduces HIV-1 infectivity.\",\n      \"method\": \"Overexpression screen, CRISPR/Cas9 knockout, capsid-nucleocapsid nanotube pulldown from cell lysates, infection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro capsid binding assay plus genetic KO with functional readout\",\n      \"pmids\": [\"28747499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SUN2 associates with lamin A/C to tether repressive nucleosomes 1 and 2 at the HIV-1 5'-LTR, blocking RNA polymerase II recruitment; SUN2 knockdown converts this chromatin to an active state, enhancing RNA Pol II phosphorylation and recruitment to the LTR, leading to HIV-1 reactivation from latency.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, TNF-α reactivation assay in HIV-latently infected cell lines\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and Co-IP with functional viral reactivation readout, multiple orthogonal methods\",\n      \"pmids\": [\"29717016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Full-length SUN2 must transition from an autoinhibited monomer to a trimer (mediated by coiled-coil domains CC1 and CC2 preceding the SUN domain) to bind KASH; MD simulations and gel filtration identify residue E452 on CC1 as important for monomer-trimer transition, and Ca2+ can drive this transition.\",\n      \"method\": \"Molecular dynamics simulation (~1 µs), gel filtration chromatography, mutagenesis of E452\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 for computational + biochemical, but no structural validation; single lab\",\n      \"pmids\": [\"29995584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SUN2-null mice develop cardiac hypertrophy with enhanced AKT/MAPK signaling but without fibrosis; in the absence of SUN2, levels of MAN1 (a negative regulator of TGFβ signaling) are elevated at the nuclear envelope, uncoupling hypertrophy from profibrotic TGFβ signaling.\",\n      \"method\": \"SUN2 knockout mouse model, cardiac histology, western blot for AKT/MAPK/TGFβ pathway components and MAN1\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined molecular pathway (MAN1/TGFβ), multiple orthogonal readouts\",\n      \"pmids\": [\"31091167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SUN2 is a component of a spliceosome complex; pulldown followed by mass spectrometry identified SUN2 as interacting with splicing factors SNRPD2, SNRPD3, and NHP2L1, and SUN2 is required for efficient sororin pre-mRNA splicing, thereby regulating sister chromatid cohesion and cell proliferation.\",\n      \"method\": \"RNAi screen, pulldown/mass spectrometry, RT-PCR for sororin intron retention, FACS, molecular imaging in TNBC cell lines\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pulldown/MS plus functional splicing assay, but single lab\",\n      \"pmids\": [\"33648524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Casein Kinase 2 phosphorylates SUN2, enabling its binding to the SCFβTrCP ubiquitin ligase; SCFβTrCP ubiquitinates SUN2, which is then extracted from the membrane by p97 AAA ATPase and degraded by the proteasome. CTDNEP1 phosphatase opposes CK2 to stabilize SUN2. Non-degradable SUN2 accumulation causes aberrant nuclear architecture, DNA damage vulnerability, and increased lagging chromosomes.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, phosphorylation assays, p97 inhibition, proteasome inhibition, CRISPR/siRNA knockdown, live-cell imaging, chromosome segregation analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstituted ubiquitination pathway with multiple orthogonal methods and functional phenotypic readouts, single rigorous paper\",\n      \"pmids\": [\"36318477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SUN2 is required for HSV-1 restriction: disruption of SUN2 (by dominant-negative constructs or RNAi) increases extracellular HSV-1 viral yields, and SUN2 has greater impact on perinuclear spacing in infected cells than SUN1, suggesting SUN2 restricts HSV-1 egress by regulating perinuclear space width.\",\n      \"method\": \"Dominant-negative SUN constructs, RNAi knockdown, viral yield assays, electron microscopy for perinuclear spacing\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic perturbation plus EM structural readout, single lab\",\n      \"pmids\": [\"35435724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ECM rigidity upregulates SUN2 expression, which promotes metaphase-to-anaphase transition by organizing astral microtubules during mitosis; on soft ECM, low SUN2 levels perturb astral microtubule organization and delay anaphase onset.\",\n      \"method\": \"Polyacrylamide gels of varying stiffness, SUN2 knockdown/overexpression, live-cell imaging of mitosis, immunofluorescence of mitotic spindle\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic link between ECM rigidity, SUN2 expression, and spindle organization demonstrated with loss- and gain-of-function plus live imaging\",\n      \"pmids\": [\"36322767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conserved cysteine residues in SUN2 undergo KASH-dependent inter- and intra-molecular disulfide bond rearrangements in the ER lumen; disruption of the terminal SUN2 disulfide bond impairs SUN2 localization, turnover, LINC complex assembly, cytoskeletal organization, and cell migration. ER lumenal components regulate SUN2 cysteine redox state.\",\n      \"method\": \"Conformation-specific antibody, biochemical disulfide trapping, KASH co-expression experiments, pharmacological and genetic ER redox perturbations, cell migration assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical disulfide mapping, conformation-specific antibody tool, and functional migration readout; multiple orthogonal methods\",\n      \"pmids\": [\"37188462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Progerin aggregation at the nuclear envelope triggers ER stress in HGPS in a SUN2-dependent manner; SUN2 clustering in the nuclear membrane is required for ER stress induction, suggesting SUN2 acts as a sensor that signals nuclear protein aggregates to the ER lumen.\",\n      \"method\": \"siRNA knockdown of SUN2, ER stress reporters, immunofluorescence of SUN2 clustering in HGPS cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined ER stress readout, but mechanism of luminal signaling not fully reconstituted\",\n      \"pmids\": [\"37210724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sun2 suppression reduces nuclear stiffness by increasing nuclear decoupling and deformability, thereby diminishing mechanical stress-induced nuclear/DNA damage in mesenchymal stromal cells; elevated Sun2 promotes RhoA activation and F-actin polymerization leading to nuclear stiffening.\",\n      \"method\": \"siRNA knockdown of Sun2 in WT and HGPS-model MSCs, cyclic mechanical stretch, nuclear deformability assays, RhoA/F-actin quantification, γH2AX measurement\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with biophysical nuclear mechanics readout and mechanistic pathway (RhoA/actin), single lab\",\n      \"pmids\": [\"37198162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SUN2 promotes flavivirus (ZIKV, DENV, JEV) replication by facilitating cytoskeleton rearrangement and replication organelle formation; SUN2 is required for interaction between actin and ZIKV NS1, and dominant-negative Nesprin-1/2 (which link SUN2 to the cytoskeleton) reduces this actin–NS1 interaction and viral replication.\",\n      \"method\": \"CRISPR/Cas9 SUN2 knockout, dominant-negative Nesprin expression, co-immunoprecipitation (actin–NS1 interaction), viral RNA synthesis assay, neonatal mouse ZIKV infection model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO plus pulldown plus in vivo infection model, multiple orthogonal methods\",\n      \"pmids\": [\"38177122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Calcium elevations trigger rapid nuclear actin assembly requiring SUN2 independently of its LINC complex function; SUN2 co-localizes and associates with the formin INF2 at the nuclear envelope in a calcium-regulated manner, and SUN2 is required for active RNA Pol II clustering in response to calcium elevations.\",\n      \"method\": \"siRNA knockdown, live-cell imaging of nuclear actin, co-immunoprecipitation of SUN2 with INF2, RNA Pol II clustering assay, calcium manipulation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function, co-IP, and functional gene expression readout with multiple orthogonal methods\",\n      \"pmids\": [\"39317734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Paclitaxel induces nuclear aberrations in interphase through SUN2-dependent disruption of lamin A/C; paclitaxel treatment causes aberrant microtubule-vimentin bundle formation, and SUN2 mediates lamin A/C reduction through polyubiquitylation. Lamin A/C levels in turn determine cell survival and recovery after drug treatment.\",\n      \"method\": \"Advanced optical imaging, electron cryo-tomography, SUN2 knockdown/knockout, ubiquitylation assays, lamin A/C quantification, cell survival assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — cryo-ET plus biochemical ubiquitylation plus genetic perturbation with multiple functional readouts\",\n      \"pmids\": [\"41367359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Sun2 is required for stiffness-dependent upregulation of extracellular matrix genes during lung fibrosis; Sun2-null fibroblasts can still become contractile myofibroblasts in response to TGFβ but fail to upregulate ECM protein-encoding genes, preventing fibrosis development in bleomycin-treated mice.\",\n      \"method\": \"Sun2-null mice, bleomycin lung fibrosis model, primary fibroblast substrate stiffness assays, gene expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with specific molecular/transcriptional readout, preprint\",\n      \"pmids\": [\"41889916\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SUN2 mediates stiffness-dependent chromatin regulation during skin fibrosis: on stiff substrates, SUN2 is required for changes in nuclear size, three distinct mechanosensitive chromatin states, and mechanical induction of the histone methyltransferase EZH2; loss of Sun2 abolishes stiffness-induced fibrotic gene expression and protects against bleomycin-induced skin fibrosis.\",\n      \"method\": \"Sun2 knockout, bleomycin skin fibrosis model, substrate stiffness experiments, chromatin state analysis, EZH2 assays in dermal fibroblasts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model plus chromatin mechanistic readout, but preprint\",\n      \"pmids\": [\"41890082\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Farnesylated prelamin A inhibits nesprin-2/SUN2 LINC complex function by reducing the diffusional mobility of nesprin-2 and SUN2, thereby impairing actin-force transmission to the nucleus and causing cell polarity defects; this effect depends on the farnesyl moiety in the prelamin A tail.\",\n      \"method\": \"FRAP for diffusional mobility, nuclear repositioning/polarity assays, expression of tail fragments and farnesylation mutants in fibroblasts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — FRAP plus functional polarity assays with mutagenesis of farnesylation site, multiple orthogonal approaches\",\n      \"pmids\": [\"42011117\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SUN2 is an inner nuclear membrane protein whose SUN domain resides in the perinuclear lumen where it forms Ca2+/disulfide-regulated trimers to interact with KASH-domain nesprins, physically linking the nucleoskeleton to the cytoskeleton (LINC complex); it is targeted to the INM via a classical NLS, a Golgi retrieval signal, and its lumenal SUN domain, and its levels are controlled by CK2/CTDNEP1-regulated SCFβTrCP-mediated ubiquitination and p97-dependent membrane extraction. Through these structural and regulatory roles, SUN2 mediates myonuclear positioning, meiotic telomere tethering, DNA damage response (via interaction with DNA-PK), mechanotransduction (transmitting ECM stiffness signals to regulate mitotic spindle formation, chromatin state via EZH2, and ECM gene expression in fibrosis), nuclear actin polymerization via association with the formin INF2 in response to calcium, TGFβ/MAN1 signaling at the nuclear lamina, and early steps of HIV and flavivirus replication.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SUN2 is an inner nuclear membrane protein that functions as a core structural component of the LINC complex, coupling the nucleoskeleton to the cytoskeleton to transduce mechanical and biochemical signals between the nucleus and the cell exterior. Its C-terminal SUN domain resides in the perinuclear lumen where it undergoes Ca²⁺- and disulfide-regulated trimerization to engage KASH-domain nesprins, while INM targeting requires a classical NLS, a Golgi-retrieval signal, and the SUN domain itself; protein levels are controlled by CK2/CTDNEP1-regulated SCFβTrCP ubiquitination followed by p97-dependent membrane extraction [PMID:15082709, PMID:20551905, PMID:29995584, PMID:37188462, PMID:36318477]. Through this nucleocytoskeletal linkage, SUN2 mediates myonuclear positioning, meiotic telomere tethering, DNA damage response signaling via interaction with DNA-PK, mechanotransduction of ECM stiffness to regulate mitotic spindle organization and chromatin state (including EZH2-dependent histone methylation), calcium-triggered nuclear actin polymerization via association with the formin INF2, and stiffness-dependent fibrotic gene expression [PMID:19509342, PMID:17452644, PMID:22863315, PMID:36322767, PMID:39317734, PMID:41890082]. SUN2 also participates in viral biology: it maintains HIV-1 latency by tethering repressive chromatin at the proviral LTR via lamin A/C, facilitates flavivirus replication organelle formation through cytoskeletal rearrangement, and restricts HSV-1 egress by regulating perinuclear space width [PMID:29717016, PMID:38177122, PMID:35435724].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that SUN2 is an inner nuclear membrane protein with its SUN domain in the perinuclear lumen resolved the basic topology and subcellular localization of this previously uncharacterized protein.\",\n      \"evidence\": \"Immunofluorescence, EM, subcellular fractionation, and GFP-tagged truncation mapping in HeLa cells\",\n      \"pmids\": [\"15082709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding partners identified\", \"Functional role unknown\", \"Mechanism of INM retention not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating SUN2 localization at meiotic telomere attachment sites established its first specialized biological function — tethering telomeres to the nuclear envelope during meiosis for bouquet formation.\",\n      \"evidence\": \"Immunolocalization and EM in mouse spermatocytes\",\n      \"pmids\": [\"17452644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Loss-of-function meiotic phenotype not yet shown\", \"Mechanism of telomere recognition not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic epistasis in Sun1/Sun2 double-knockout mice revealed that SUN proteins are collectively required to retain Nesprin-1 at the nuclear envelope and position myonuclei, establishing the LINC complex as essential for nuclear-cytoskeletal coupling in muscle.\",\n      \"evidence\": \"Sun1⁻/⁻, Sun2⁻/⁻, and double-KO mice with histology and IF\",\n      \"pmids\": [\"19509342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of SUN2 vs SUN1 not fully separated\", \"Molecular basis of force transmission not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Systematic mutagenesis revealed that INM targeting of SUN2 requires three cooperating signals — a classical NLS, an arginine-based Golgi retrieval motif, and the lumenal SUN domain — explaining how the protein navigates the secretory pathway to reach the inner nuclear membrane.\",\n      \"evidence\": \"Deletion/mutation analysis with fluorescence localization in human cells\",\n      \"pmids\": [\"20551905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of Golgi retrieval receptor/coatomer interaction not fully characterized\", \"Kinetics of INM targeting not measured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two concurrent advances linked SUN2 to genome integrity: interaction with DNA-PK and a requirement for ATM/γH2AX activation in double-KO MEFs established SUN proteins as components of the DNA damage response, while studies in laminopathy cells showed SUN2 organization depends on prelamin A farnesylation status.\",\n      \"evidence\": \"Co-IP screen, Sun1/2 double-KO MEFs with DDR readouts; IF and pharmacological rescue in MADA patient fibroblasts\",\n      \"pmids\": [\"22863315\", \"22706480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SUN2 directly contacts DNA-PK or acts through lamin scaffolding unknown\", \"Mechanism by which prelamin A farnesylation disrupts SUN2 lattice not defined at structural level\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Disease-associated SUN1/SUN2 variants impaired nuclear repositioning and microtubule nucleation at the nuclear envelope, providing the first human-genetics evidence that LINC complex dysfunction contributes to muscle disease pathogenesis.\",\n      \"evidence\": \"Nuclear repositioning assays in patient fibroblasts and myotubes expressing SUN variants\",\n      \"pmids\": [\"25210889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise structural basis of variant pathogenicity not resolved\", \"Whether SUN2 variants alone are sufficient to cause disease unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Multiple studies converged on a role for SUN2 in early HIV-1 infection, showing that overexpressed SUN2 blocks HIV nuclear import in a capsid- and CypA-dependent manner, while endogenous SUN2 in primary T cells supports wild-type HIV reverse transcription and nuclear entry.\",\n      \"evidence\": \"Overexpression/knockdown, CypA perturbation, viral passaging, infection assays in cell lines and primary CD4⁺ T cells\",\n      \"pmids\": [\"26865710\", \"27149839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contradictory gain-of-function vs loss-of-function outcomes not fully reconciled\", \"Direct physical interaction with capsid in cells not demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Further work clarified that SUN2 silencing in primary T cells reduces HIV infection indirectly by impairing T cell activation and proliferation, while in vitro capsid-nanotube pulldowns confirmed a direct SUN2-capsid physical interaction, partially resolving the apparent contradictions.\",\n      \"evidence\": \"siRNA knockdown with activation/proliferation assays in primary T cells; capsid-nucleocapsid nanotube pulldown plus CRISPR KO\",\n      \"pmids\": [\"28077629\", \"28747499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the capsid interaction is physiologically relevant during natural infection remains debated\", \"In vivo HIV infection in SUN2 KO model not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ChIP experiments revealed that SUN2, together with lamin A/C, tethers repressive nucleosomes at the HIV-1 5ʹ-LTR to maintain proviral latency, establishing a chromatin-level mechanism for SUN2's impact on HIV gene expression distinct from its nuclear import role.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA knockdown with TNF-α reactivation in latently infected cell lines\",\n      \"pmids\": [\"29717016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this latency mechanism operates in primary reservoir cells in vivo unknown\", \"How SUN2 is recruited specifically to the LTR not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Biochemical and computational analysis showed that full-length SUN2 exists as an autoinhibited monomer that undergoes Ca²⁺-driven trimerization via coiled-coil domains CC1/CC2, a prerequisite for KASH engagement — revealing an activation switch for LINC complex assembly.\",\n      \"evidence\": \"Molecular dynamics simulation, gel filtration, E452 mutagenesis\",\n      \"pmids\": [\"29995584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure of full-length SUN2 trimer\", \"In vivo Ca²⁺ regulation of trimerization not demonstrated\", \"Autoinhibition mechanism not validated by structural biology\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SUN2-null mice developed cardiac hypertrophy with enhanced AKT/MAPK signaling but without fibrosis due to elevated MAN1 that suppresses TGFβ, demonstrating that SUN2 modulates the coupling between hypertrophic and fibrotic signaling at the nuclear lamina.\",\n      \"evidence\": \"SUN2 KO mice with cardiac histology, western blots for AKT/MAPK/TGFβ/MAN1\",\n      \"pmids\": [\"31091167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SUN2 directly regulates MAN1 levels or indirectly through NE reorganization is unknown\", \"Heart-specific conditional KO not performed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mass spectrometry identified SUN2 as an interactor of spliceosome components (SNRPD2, SNRPD3, NHP2L1), and SUN2 depletion caused sororin intron retention, linking SUN2 to pre-mRNA splicing regulation and consequently to sister chromatid cohesion.\",\n      \"evidence\": \"Pulldown/MS, RT-PCR for splicing, FACS in TNBC cell lines\",\n      \"pmids\": [\"33648524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SUN2 is a stable spliceosome component or an indirect regulator unclear\", \"Not replicated in non-cancer cell types\", \"Mechanism of SUN2 action on splicing not reconstituted\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A complete degradation pathway was reconstituted: CK2 phosphorylates SUN2 to create a degron recognized by SCFβTrCP, leading to ubiquitination and p97-dependent membrane extraction for proteasomal degradation, with CTDNEP1 opposing CK2 — establishing how SUN2 abundance is dynamically controlled and why its dysregulation causes nuclear architecture defects and chromosome missegregation.\",\n      \"evidence\": \"Co-IP, in vivo/in vitro ubiquitination, phosphorylation assays, p97/proteasome inhibition, CRISPR/siRNA, live-cell imaging of chromosome segregation\",\n      \"pmids\": [\"36318477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-cycle timing of CK2/CTDNEP1 regulation not mapped\", \"Whether this pathway is tissue-specific is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Two parallel discoveries linked SUN2 to mechanotransduction and viral defense: ECM stiffness upregulates SUN2 to organize astral microtubules during mitosis, and SUN2 restricts HSV-1 egress by maintaining perinuclear space width.\",\n      \"evidence\": \"Variable-stiffness gels with live mitotic imaging and SUN2 perturbation; dominant-negative constructs and RNAi with HSV-1 yield and EM of perinuclear spacing\",\n      \"pmids\": [\"36322767\", \"35435724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ECM stiffness transcriptionally upregulates SUN2 is not defined\", \"Whether SUN2's perinuclear spacing role is relevant for HSV-1 in vivo unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple 2023 studies revealed that SUN2 functions as a biophysical sensor: its lumenal disulfide bonds undergo KASH-dependent redox rearrangements essential for LINC assembly and cell migration; SUN2 clustering transduces progerin aggregation into ER stress in HGPS; and SUN2 levels regulate nuclear stiffness and mechanically-induced DNA damage via RhoA/F-actin.\",\n      \"evidence\": \"Disulfide trapping and conformation-specific antibody with migration assays; siRNA of SUN2 with ER stress reporters in HGPS cells; siRNA with nuclear deformability/γH2AX in MSCs under cyclic stretch\",\n      \"pmids\": [\"37188462\", \"37210724\", \"37198162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of ER oxidoreductase controlling SUN2 redox state unknown\", \"Mechanism of SUN2 clustering-to-ER stress signal transduction not reconstituted\", \"Whether reducing SUN2 is therapeutically viable in HGPS untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SUN2 was shown to promote flavivirus replication by facilitating cytoskeletal rearrangement and replication organelle formation through actin–NS1 interaction, and independently to mediate calcium-triggered nuclear actin polymerization via the formin INF2 — revealing LINC-independent nuclear functions.\",\n      \"evidence\": \"CRISPR KO with co-IP (actin–NS1) and in vivo ZIKV model; siRNA with live nuclear actin imaging, co-IP of SUN2–INF2, calcium manipulation\",\n      \"pmids\": [\"38177122\", \"39317734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SUN2 recruits INF2 specifically at the nuclear envelope not structurally resolved\", \"Whether SUN2–INF2 function is relevant for endogenous nuclear actin beyond calcium signaling unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Recent work expanded SUN2's mechanotransduction role to fibrosis and drug response: SUN2 mediates stiffness-dependent ECM gene induction and EZH2-regulated chromatin remodeling in fibrosis, transmits paclitaxel-induced microtubule forces to cause lamin A/C polyubiquitylation and nuclear damage, and farnesylated prelamin A impairs LINC complex function by reducing SUN2/nesprin-2 mobility.\",\n      \"evidence\": \"Sun2 KO mice in bleomycin lung and skin fibrosis models with chromatin/transcription analysis; cryo-ET plus ubiquitylation assays with SUN2 KO in paclitaxel-treated cells; FRAP and polarity assays with farnesylation mutants\",\n      \"pmids\": [\"41890082\", \"41889916\", \"41367359\", \"42011117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SUN2-dependent fibrotic mechanism is shared across all organ fibroses unknown\", \"The ubiquitin ligase mediating SUN2-dependent lamin A/C degradation during paclitaxel treatment not identified\", \"Therapeutic potential of targeting SUN2 in fibrosis or chemoresistance untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of full-length SUN2 autoinhibition and trimerization, how ECM stiffness signals are transduced to SUN2 transcriptional upregulation, the identity of ER oxidoreductases controlling SUN2 disulfide switches, and whether tissue-specific SUN2 functions can be therapeutically targeted in fibrosis, laminopathies, or viral infection.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length SUN2 structure available\", \"Upstream mechanotransduction pathway to SUN2 expression undefined\", \"In vivo therapeutic targeting not explored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 13, 19]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 18, 21, 22]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [18, 20, 21, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 3, 6, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 12, 23]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [19, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 21, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [25, 26]}\n    ],\n    \"complexes\": [\n      \"LINC complex\"\n    ],\n    \"partners\": [\n      \"SYNE1\",\n      \"SYNE2\",\n      \"SUN1\",\n      \"LMNA\",\n      \"DNA-PKcs\",\n      \"INF2\",\n      \"BTRC\",\n      \"CSNK2A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}