Affinage

SHARPIN

Sharpin · UniProt Q9H0F6

Length
387 aa
Mass
39.9 kDa
Annotated
2026-06-10
91 papers in source corpus 43 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHARPIN is a multifunctional adaptor that operates as an essential accessory subunit of the linear ubiquitin chain assembly complex (LUBAC) and, separately, as a LUBAC-independent regulator of integrin activation and cytoskeletal dynamics (PMID:21455181, PMID:21455180, PMID:21947080). Within LUBAC, SHARPIN binds HOIP (RNF31) and HOIL-1L (RBCK1) and stimulates formation of Met1-linked linear ubiquitin chains on NEMO to activate canonical NF-κB signaling (PMID:21455181, PMID:21455180); this requires its central UBL domain interaction with the HOIP UBA domain (strengthened by an accessory N-terminal UBL domain), its NZF domain (which binds both linear and K63-linked chains to recruit LUBAC to the activated TNFR complex), and phosphorylation at S165 (PMID:34965468, PMID:26976635, PMID:39528476, PMID:33392484). Beyond promoting inflammation-resolving signaling, SHARPIN restrains TNF-driven cell death: its loss sensitizes cells to FADD/caspase-8-dependent apoptosis and, in mice, drives RIPK1-kinase-dependent, TNFR1/TRADD/FADD-mediated keratinocyte death and CYLD-deubiquitinase-dependent RIPK1 recruitment to death-signaling complex II (PMID:21455181, PMID:24821972, PMID:25443632, PMID:25443631, PMID:34887354). Independently of LUBAC, SHARPIN binds integrin α-subunit cytoplasmic tails (β1, αIIbβ3, αLβ2/LFA-1) through the same UBL surface used for RNF31, holding integrins inactive by blocking talin/kindlin recruitment and thereby controlling cell adhesion, lymphocyte uropod detachment, and platelet activation (PMID:21947080, PMID:26600301, PMID:31429758, PMID:24210817, PMID:30804189, PMID:34991155). SHARPIN also promotes ARP2/3-dependent lamellipodium formation via ERK-controlled S146 phosphorylation (PMID:28775156, PMID:36148554), and was first identified as a SHANK-interacting postsynaptic density protein (PMID:11178875). Biallelic SHARPIN loss in humans causes attenuated NF-κB responses, TNF-superfamily-induced cell death, and autoinflammation that resolves on anti-TNF therapy (PMID:38609546).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2001 High

    Established the first molecular identity and localization of SHARPIN by showing it is a postsynaptic density protein that binds SHANK and self-associates, defining its modular architecture before any signaling role was known.

    Evidence Yeast two-hybrid, reciprocal Co-IP from brain and heterologous cells, colocalization, and domain mapping

    PMID:11178875

    Open questions at the time
    • Functional consequence of SHANK binding at synapses not defined
    • No link to later ubiquitin/integrin roles established here
  2. 2011 High

    Defined SHARPIN's central mechanism by showing it is a LUBAC subunit that stimulates HOIP-dependent linear ubiquitination of NEMO to activate NF-κB, explaining the autoinflammatory phenotype of SHARPIN loss.

    Evidence Co-IP, in vitro linear ubiquitination reconstitution, NF-κB reporter, SHARPIN-deficient primary cells; two simultaneous Nature papers

    PMID:21455180 PMID:21455181

    Open questions at the time
    • Did not resolve which SHARPIN domains mediate HOIP binding versus chain stimulation
    • Substrates beyond NEMO not enumerated
  3. 2011 High

    Separated SHARPIN's anti-apoptotic function from its NF-κB role by showing its loss sensitizes cells to TNF-induced FADD/caspase-8-dependent death independently of transcriptional activation.

    Evidence TNF-α stimulation of SHARPIN-deficient cells with FADD/caspase-8 genetic epistasis

    PMID:21455181

    Open questions at the time
    • Upstream complex composition driving death not fully mapped here
    • Relationship to necroptosis not yet addressed
  4. 2011 High

    Revealed a LUBAC-independent function: SHARPIN is an endogenous integrin inhibitor that binds α-subunit tails and blocks the talin/kindlin-driven activation switch, linking it to cell adhesion control.

    Evidence RNAi screen, direct binding assay, SHARPIN-deficient primary cells with rescue, integrin activity assays

    PMID:21947080

    Open questions at the time
    • Molecular details of how binding excludes talin/kindlin not yet resolved
    • Domain responsible for integrin binding not mapped here
  5. 2012 High

    Provided structural insight by showing the N-terminal region adopts a PH superfold serving as a dimerization module rather than a ligand-binding domain.

    Evidence X-ray crystallography (2.0–2.6 Å) of the N-terminal SHARPIN domain

    PMID:22549881

    Open questions at the time
    • Functional role of dimerization in LUBAC or integrin contexts not tested
    • No structure of central UBL or NZF domains in this study
  6. 2013 High

    Extended integrin regulation to motility by showing SHARPIN localizes to the migrating-lymphocyte uropod and keeps LFA-1 inactive to permit trailing-edge detachment.

    Evidence Live imaging, migration assays on ICAM-1, direct binding, rescue, integrin activation measurement

    PMID:24210817

    Open questions at the time
    • How SHARPIN is targeted to the uropod not defined
    • Interplay with LUBAC at the rear edge not addressed
  7. 2014 High

    Placed RIPK1 kinase activity downstream of SHARPIN loss in vivo, showing kinase-dead RIPK1 fully rescues cpdm pathology and implicating necroptotic/death signaling in the disease.

    Evidence Genetic epistasis with Ripk1(K45A) knock-in crossed to cpdm mice; necroptosis assays

    PMID:24821972

    Open questions at the time
    • Biochemical basis of RIPK1 hyperactivation upon SHARPIN loss not yet defined here
    • Cell-type drivers not pinpointed
  8. 2014 High

    Dissected the cell-death axis driving cpdm skin inflammation, showing TNFR1- and TRADD/FADD-mediated keratinocyte apoptosis (with RIPK3) is the trigger.

    Evidence Compound knockout genetic epistasis crossed to Sharpin-deficient mice; two independent studies

    PMID:25443631 PMID:25443632

    Open questions at the time
    • Contribution of non-keratinocyte compartments not resolved
    • Apoptosis vs necroptosis balance across tissues left open
  9. 2014 Medium

    Identified a ubiquitin-ligase-like activity by showing SIPL1/SHARPIN promotes K63-linked PTEN polyubiquitination via its UBL domain, expanding its substrate repertoire.

    Evidence Co-IP with ubiquitin linkage mutants and UBL deletion constructs, ubiquitination assays

    PMID:25152374

    Open questions at the time
    • No catalytic mechanism defined for SHARPIN itself
    • Single lab, no in vitro reconstitution
  10. 2015 Medium

    Connected SHARPIN to adaptive immunity by showing K63-ubiquitinated SHARPIN inhibits TCRζ–ZAP70 association, regulating Treg generation and homeostasis.

    Evidence Co-IP, ubiquitination assays, SHARPIN-deficient T cell signaling, Treg transfer

    PMID:26829767

    Open questions at the time
    • Ligase generating SHARPIN K63 chains not identified
    • Single lab
  11. 2016 Medium

    Mapped competing binding surfaces, showing the UBL domain engages integrin α-tails and RNF31 mutually exclusively, providing a molecular switch between SHARPIN's LUBAC and integrin functions.

    Evidence Site-directed mutagenesis (V267/L276 shared; F263/I272 RNF31-specific), competition and functional assays

    PMID:26600301

    Open questions at the time
    • Cellular signal controlling partner choice unknown
    • Single lab
  12. 2016 Medium

    Defined the SHARPIN NZF domain as the key element for cell-death protection through K63/linear chain binding that recruits LUBAC to the activated TNFR complex, distinguishing it from HOIL-1L NZF.

    Evidence HOIL-1L/SHARPIN double-knockout intercross, NZF mutants, TNFR recruitment and death assays

    PMID:26976635

    Open questions at the time
    • Structural basis of dual chain recognition not resolved here
    • Single lab
  13. 2016 Medium

    Identified caspase-1 as a LUBAC-independent target, with SHARPIN disrupting p20/p10 dimerization to limit IL-1β/IL-18 maturation.

    Evidence Co-IP, caspase-1 processing assay, sepsis model, caspase-1 inhibitor rescue

    PMID:26968342

    Open questions at the time
    • Reconciliation with reports of impaired inflammasome priming in SHARPIN-deficient macrophages not addressed
    • Single lab
  14. 2016 High

    Placed CYLD as a required effector of SHARPIN-loss pathology, showing reduced inhibitory CYLD-S418 phosphorylation enhances RIPK1 deubiquitination and complex-II recruitment.

    Evidence Sharpin/Cyld double-knockout epistasis, TNFR complex IP, CYLD phosphorylation assays, conditional Cyld deletion

    PMID:34887354

    Open questions at the time
    • Kinase controlling CYLD-S418 phosphorylation not identified
    • How SHARPIN loss alters this phosphorylation mechanistically left open
  15. 2017 Medium

    Identified a LUBAC-independent enzymatic-enhancer role: SHARPIN binds PRMT5 and stimulates its methyltransferase activity to control SOX10/MITF via SKI, linking SHARPIN to melanoma gene expression.

    Evidence Co-IP, PRMT5 activity assay, SKI dimethylation assay, knockdown/overexpression in melanoma cells

    PMID:29227283

    Open questions at the time
    • Structural basis of PRMT5 activation unknown
    • Single lab
  16. 2017 Medium

    Defined a cytoskeletal effector role by showing SHARPIN binds the ARP2/3 complex to drive lamellipodium formation independently of LUBAC.

    Evidence Interactome MS, Co-IP, ARP2/3-binding-deficient mutant, lamellipodium assay

    PMID:28775156

    Open questions at the time
    • Regulation of the SHARPIN–ARP2/3 interaction not yet defined here
    • Single lab
  17. 2017 Medium

    Established a tissue-context function in stroma, showing stromal SHARPIN controls collagen assembly, contraction and degradation required for mammary ductal outgrowth.

    Evidence Stromal-specific (S100a4-Cre) knockout, mammary transplantation, collagen and ECM stiffness assays

    PMID:27974362

    Open questions at the time
    • Molecular mediator of collagen-handling defect not identified
    • Single lab
  18. 2019 Medium

    Resolved the integrin-inhibition mechanism, showing SHARPIN forms a complex with kindlin-1 on the β1 tail that blocks talin head binding.

    Evidence GST pulldown, Co-IP, talin competition, cell-based β1 activation assay

    PMID:31429758

    Open questions at the time
    • Apparent tension with earlier model of SHARPIN blocking kindlin recruitment not reconciled
    • Single lab
  19. 2019 Medium

    Extended integrin regulation and LUBAC signaling to platelets, showing SHARPIN binds the αIIb tail and contributes to agonist-induced Met1 ubiquitination of NEMO, restraining fibrinogen binding.

    Evidence Co-IP/pulldown, super-resolution microscopy, knockdown in iPS-derived megakaryocytes/platelets, ubiquitination assays

    PMID:30804189

    Open questions at the time
    • In vivo platelet phenotype not yet established in this study
    • Single lab
  20. 2020 Medium

    Identified S165 phosphorylation as a positive regulatory mark required for efficient linear ubiquitination of NEMO and NF-κB activation.

    Evidence MS phosphosite identification, S165A mutant analysis, NEMO ubiquitination and NF-κB assays

    PMID:33392484

    Open questions at the time
    • Kinase responsible for S165 phosphorylation not identified
    • Single lab
  21. 2022 High

    Confirmed the platelet role in vivo, showing platelet-specific SHARPIN deletion increases αIIbβ3/talin colocalization and fibrinogen binding while reducing NF-κB activation and inflammation.

    Evidence Platelet-specific conditional knockout, super-resolution imaging, fibrinogen and ubiquitination assays, colitis/peritonitis models

    PMID:34991155

    Open questions at the time
    • Relative contributions of integrin vs LUBAC functions to the inflammation phenotype not separated
    • Same lab lineage as prior platelet work
  22. 2022 Medium

    Defined the regulatory logic of SHARPIN's cytoskeletal function, showing ERK1/2-driven (PP2A-reversed) S146 phosphorylation gates ARP2/3 binding, lamellipodia, and metastasis.

    Evidence Phosphoproteomics, in vitro kinase assay, CRISPR knockout with S146A rescue, 3D invasion and zebrafish metastasis

    PMID:36148554

    Open questions at the time
    • Structural mechanism of phospho-dependent ARP2/3 engagement unknown
    • Single lab
  23. 2022 Medium

    Refined the LUBAC-architecture model, showing the N-terminal UBL domain does not join LUBAC but stabilizes the central UBL domain and strengthens its binding to the HOIP UBA domain.

    Evidence Size exclusion chromatography, circular dichroism, unfolding assays, biosensor binding

    PMID:34965468

    Open questions at the time
    • No mutagenesis to test the stabilization model in cells
    • Single lab
  24. 2023 High

    Provided structural detail of SHARPIN self-association, showing LTM-motif homodimerization shared with HOIL-1L, with a disease-associated HOIL-1L mutation disrupting the fold.

    Evidence Crystal structures of SHARPIN and HOIL-1L LTM homodimers with A18P mutagenesis

    PMID:37976837

    Open questions at the time
    • Functional consequence of SHARPIN LTM dimerization in LUBAC not tested
    • Single lab
  25. 2024 High

    Established SHARPIN as a human disease gene, showing biallelic loss attenuates NF-κB, sensitizes cells to TNF-superfamily death, and causes autoinflammation reversible by anti-TNF therapy.

    Evidence Patient fibroblasts/B cells NF-κB and death assays; anti-TNF clinical intervention with transcriptomic resolution

    PMID:38609546

    Open questions at the time
    • Full spectrum of human phenotypes not yet defined
    • Genotype–phenotype relationships across variants not established
  26. 2024 Medium

    Refined the division of labor between LUBAC NZF domains, showing SHARPIN NZF protects against cell death largely independent of chain type while HOIL-1L NZF linear-chain binding drives full NF-κB activation.

    Evidence NZF ubiquitin-binding assays, compound NZF mutants, NF-κB and death readouts, inhibitor screen

    PMID:39528476

    Open questions at the time
    • Structural basis of SHARPIN NZF chain-type promiscuity not resolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SHARPIN's many LUBAC-independent activities (integrin inhibition, caspase-1 suppression, PRMT5 activation, ARP2/3-driven motility, and multiple substrate ubiquitination/stabilization events) are coordinated and spatially partitioned within a single cell remains unresolved.
  • No unifying framework linking competing UBL-domain engagements in vivo
  • Signals switching SHARPIN between LUBAC and non-LUBAC pools unknown
  • Most cancer-context substrate findings rest on single labs without reconstitution

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-109582 Hemostasis 2 R-HSA-392499 Metabolism of proteins 2
Partners
ACTR2/3IKBKGITGA2BITGB1PRMT5RBCK1RNF31SHANK
Complex memberships
LUBAC

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SHARPIN directly interacts with the ankyrin repeats of SHANK family proteins and is enriched in the postsynaptic density (PSD) of excitatory synapses; the C-terminal half of SHARPIN mediates SHANK binding while the N-terminal half mediates homomultimerization. Yeast two-hybrid, co-immunoprecipitation from brain and heterologous cells, immunostaining/colocalization Molecular and cellular neurosciences High 11178875
2011 SHARPIN is a component of the linear ubiquitin chain assembly complex (LUBAC) together with HOIP (RNF31) and HOIL-1L (RBCK1); binding to HOIP stimulates formation of linear (Met1-linked) ubiquitin chains in vitro and in vivo, leading to linear ubiquitination of NEMO and activation of NF-κB signaling. Co-immunoprecipitation, in vitro ubiquitination assay, NF-κB reporter assay, SHARPIN-deficient mouse embryonic fibroblasts/B cells/macrophages Nature High 21455180 21455181
2011 SHARPIN deficiency sensitizes cells to TNF-α-induced apoptosis via FADD- and caspase-8-dependent pathways, demonstrating that SHARPIN inhibits apoptosis independently of NF-κB activation. TNF-α stimulation of SHARPIN-deficient MEFs and primary cells; caspase-8/FADD genetic epistasis; cell death assays Nature High 21455181
2011 SHARPIN is an endogenous inhibitor of β1-integrin activation; it directly binds to a conserved cytoplasmic region of integrin α-subunits and inhibits recruitment of talin and kindlin to the integrin, preventing the inactive-to-active conformational switch. RNAi screen, direct binding assay, fibroblasts/leukocytes/keratinocytes from SHARPIN-deficient mice, rescue by SHARPIN re-expression, integrin activity assays Nature cell biology High 21947080
2011 SHARPIN negatively associates with TRAF2-mediated NF-κB activation; mass spectrometry identified TRAF2 as a SHARPIN co-immunoprecipitated partner, and overexpression studies show SHARPIN can negatively modulate NF-κB via TRAF2 interaction. Co-immunoprecipitation, mass spectrometry, NF-κB luciferase reporter assay PloS one Low 21829440
2011 SHARPIN interacts with NEMO (IKBKG) in macrophages; SHARPIN deficiency impairs NEMO-dependent signaling (p105 and ERK phosphorylation, p65 nuclear localization) downstream of TLR2, and this interaction is abrogated by the panr2 (L153P) NEMO mutation. Systems biology, co-immunoprecipitation, transcriptome analysis of SHARPIN-deficient macrophages Proceedings of the National Academy of Sciences of the United States of America Medium 21709223
2011 SHARPIN deficiency in keratinocytes leads to apoptosis via the intrinsic mitochondrial pathway (caspase-9 and caspase-3 activation, Bax/Bcl2 shift, mitochondrial membrane potential loss) rather than the extrinsic caspase-8 pathway. Annexin-V/PI FACS, transmission electron microscopy, caspase activity assays, western blotting in SHARPIN-deficient mouse skin Journal of dermatological science Medium 21620685
2012 The N-terminal portion of SHARPIN adopts a pleckstrin homology (PH) superfold that functions as a dimerization module rather than a ligand-binding domain; crystal structure determined to 2.0–2.6 Å resolution. X-ray crystallography (crystal structure of N-terminal SHARPIN domain) The Journal of biological chemistry High 22549881
2013 SHARPIN localizes to the trailing edge (uropod) of migrating lymphocytes and directly interacts with LFA-1 (αLβ2 integrin), maintaining LFA-1 in an inactive state to enable uropod detachment and control lymphocyte migration velocity. Live imaging, SHARPIN-deficient lymphocyte migration assays on ICAM-1, direct binding assay, rescue by SHARPIN re-expression, integrin activation measurement Cell reports High 24210817
2014 RIP1 (RIPK1) kinase activity is required for the inflammatory pathology in SHARPIN-deficient (cpdm) mice; kinase-dead Ripk1(K45A) completely protected against all cpdm-related pathology, placing RIPK1 kinase downstream of SHARPIN loss in TNF-driven inflammation. Genetic epistasis: Ripk1(K45A) knock-in mice crossed with cpdm mice; in vivo and in vitro necroptosis assays Journal of immunology High 24821972
2014 Skin inflammation in SHARPIN-deficient mice is driven primarily by TNFR1 (but not TNFR2), and is dependent on TRADD- and FADD-mediated keratinocyte apoptosis; epidermis-restricted ablation of FADD combined with RIPK3 deficiency fully prevented skin inflammation. Genetic epistasis: compound knockout mice (Tnfr1-/-, Ripk3-/-, Casp8+/-, Fadd-/- keratinocyte-specific) crossed with Sharpin-deficient mice eLife High 25443631 25443632
2015 SHARPIN regulates TCR signaling in T cells; SHARPIN is conjugated with K63-linked ubiquitin chains, which inhibits the association of TCRζ with ZAP70, thereby affecting regulatory T cell generation and maintaining immunological homeostasis. Co-immunoprecipitation, ubiquitination assays, SHARPIN-deficient T cell signaling analysis, Treg transfer experiments Nature immunology Medium 26829767
2015 SHARPIN is required for optimal NLRP3 inflammasome activation; SHARPIN-deficient macrophages show defects in canonical and non-canonical NLRP3 inflammasome activation, associated with impaired NF-κB and MAPK pathway priming. Loss-of-function analysis using Sharpin(cpdm) macrophages, NLRP3 inflammasome activation assays Journal of immunology Medium 25637014
2015 SHARPIN binds integrin α-subunit cytoplasmic tails and LUBAC component RNF31 in a mutually exclusive manner via its ubiquitin-like (UBL) domain; residues V267 and L276 are required for both interactions, while F263 and I272 are specifically required for RNF31 but not integrin binding. Binding assays with SHARPIN mutants, competition assays with integrin α-tail and RNF31, NF-κB reporter assay, integrin activity assay PloS one Medium 26600301
2016 SHARPIN directly binds caspase-1 in a LUBAC-independent manner and disrupts p20/p10 dimer formation (the final step of caspase-1 processing), thereby inhibiting caspase-1 enzyme activation and maturation of IL-1β/IL-18. Co-immunoprecipitation of SHARPIN with caspase-1, caspase-1 processing assay, Sharpin-deficient mouse sepsis model, caspase-1 inhibitor rescue The American journal of pathology Medium 26968342
2016 The NZF domain of SHARPIN (but not that of HOIL-1L) is critical for protection from programmed cell death by enhancing LUBAC recruitment to the activated TNFR complex; SHARPIN NZF binds K63-linked ubiquitin chains (in addition to linear chains), and this K63-binding activity is involved in LUBAC recruitment. Intercross of HOIL-1L and SHARPIN knockout mice, NZF domain mutants, TNFR complex recruitment assays, cell death assays Molecular and cellular biology Medium 26976635
2016 Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD deubiquitinase; loss of SHARPIN impairs phosphorylation of CYLD at serine 418 (which normally inhibits CYLD activity), leading to enhanced CYLD-mediated removal of ubiquitin from RIPK1 and increased RIPK1 recruitment to death-signaling Complex II upon TNF stimulation. Genetic epistasis (Sharpin/Cyld double knockout), TNFR complex immunoprecipitation, CYLD phosphorylation assays, conditional Cyld deletion Proceedings of the National Academy of Sciences of the United States of America High 34887354
2016 SHARPIN regulates mammary gland stromal function; mice with stromal-specific (S100a4-Cre) deletion of Sharpin have reduced ductal outgrowth and defects in collagen fibre assembly, contraction and degradation, while transplanted SHARPIN-null mammary epithelial cells in wild-type stroma develop normally. Conditional knockout (S100a4-Cre), mammary gland transplantation, collagen contraction/degradation assays, ECM stiffness measurement The EMBO journal Medium 27974362
2017 SHARPIN interacts with PRMT5 (protein arginine methyltransferase 5) in a LUBAC-independent manner and increases PRMT5 methyltransferase activity; activated PRMT5 controls SOX10 and MITF expression via arginine dimethylation and inhibition of the transcriptional corepressor SKI. Co-immunoprecipitation, PRMT5 methyltransferase activity assay, SKI arginine dimethylation assay, SOX10/MITF expression analysis, SHARPIN knockdown/overexpression in melanoma cells The Journal of clinical investigation Medium 29227283
2017 SHARPIN promotes p53 polyubiquitination and degradation in an MDM2-dependent manner; SHARPIN associates with MDM2, prolongs MDM2 protein stability, and facilitates p53 poly-ubiquitination. Co-immunoprecipitation, ubiquitination assay, p53 stability assay, SHARPIN depletion with rescue by p53 knockdown in breast cancer cell lines Neoplasia Medium 28063307
2017 SHARPIN stabilizes estrogen receptor α (ERα) protein by inhibiting ERα poly-ubiquitination and facilitating ERα mono-ubiquitination at K302/303 sites; SHARPIN interacts with ERα in both cytosol and nucleus. Co-immunoprecipitation, ubiquitination assays, ERE luciferase reporter, SHARPIN knockdown/overexpression, ERα stability assays Oncotarget Medium 29100376
2017 SHARPIN interacts with ARP2/3 complex and promotes lamellipodium formation in a LUBAC-independent manner; the ARP2/3-binding site on SHARPIN was identified and an ARP2/3-binding-deficient SHARPIN mutant failed to support lamellipodia. Mass spectrometry interactome (Sharpin interactome), co-immunoprecipitation, site-directed mutagenesis, lamellipodium formation assay Journal of cell science Medium 28775156
2017 SHARPIN promotes Versican expression synergistically with Wnt/β-catenin pathway activation to drive hepatocellular carcinoma invasion. Stable SHARPIN-overexpressing cell lines, microarray analysis, Wnt/β-catenin reporter assay, invasion assays, Versican knockdown, in vivo tumor xenograft Oncogenesis Low 27941932
2017 A novel SHARPIN-PRMT5-H3R2me1 axis regulates lung cancer cell invasion; SHARPIN-PRMT5 complex catalyzes monomethylation of histone H3 arginine 2 (H3R2me1) at metastasis-related gene loci, which is linked to H3K4me3 via MLL complex components ASH2 and WDR5. Co-immunoprecipitation, histone methylation assays, chromatin immunoprecipitation, SHARPIN knockdown in lung cancer cells Oncotarget Low 28903384
2019 SHARPIN suppresses β1-integrin activation by forming a complex with kindlin-1 and the integrin β1 cytoplasmic tail; SHARPIN directly binds the β1 CT and the sharpin-kindlin-1 complex inhibits talin head domain binding to the β1 CT. Biochemical binding assays (GST pulldown, co-immunoprecipitation), cell-based β1-integrin activation assay, talin competition assay Cell communication and signaling Medium 31429758
2019 SHARPIN interacts with αIIb cytoplasmic tail of integrin αIIbβ3 in human platelets and participates in LUBAC-mediated Met1 linear ubiquitination of NEMO upon platelet stimulation; SHARPIN knockdown in megakaryocytes/platelets increases basal and agonist-induced fibrinogen binding and reduces Met1 ubiquitination and NF-κB activation. Co-immunoprecipitation and pull-down assays, super-resolution microscopy, SHARPIN knockdown in iPS-derived megakaryocytes/platelets, ubiquitination assays Proceedings of the National Academy of Sciences of the United States of America Medium 30804189
2019 SHARPIN promotes melanoma migration and invasion by upregulating Rap1 GTPase expression and activating downstream p38 and JNK/c-Jun pathways; Rap1 activator/inhibitor treatments partially rescued invasion phenotypes. SHARPIN knockdown/overexpression in melanoma cells, invasion/migration assays, Rap1 pharmacological modulation, in vivo metastasis models The Journal of investigative dermatology Low 31401046
2019 SHARPIN inhibits YAP protein in esophageal squamous cell carcinoma; SHARPIN associates with YAP and promotes YAP K48-dependent poly-ubiquitination and proteasomal degradation, thereby suppressing Hippo pathway target genes (CTGF, CYR61). Co-immunoprecipitation, ubiquitination assay, YAP protein stability assay, SHARPIN/YAP knockdown rescue experiments, TEAD reporter Neoplasia Medium 31884247
2019 SHARPIN interacts with Eya1 (Eyes absent 1) and enhances Eya1 function as a coactivator for Six transcription factors; this interaction is required for normal zebrafish ear and branchial arch development. GST pulldown, co-immunoprecipitation, Six/Eya coactivation assay, zebrafish morpholino knockdown Molecular and cellular biology Medium 20956555
2020 SHARPIN phosphorylation at serine 165 is required for optimal NF-κB activation; a phosphorylation-resistant S165A mutant shows impaired linear ubiquitination of NEMO and reduced NF-κB activation in response to TNFα. Mass spectrometry identification of phosphorylation site, phosphorylation-resistant mutant analysis, NEMO ubiquitination assay, NF-κB reporter assay iScience Medium 33392484
2020 SHARPIN stabilizes β-catenin protein by competing with the E3 ubiquitin ligase β-TrCP1 for β-catenin binding, thereby reducing β-catenin K48-linked ubiquitination and proteasomal degradation in a linear ubiquitination-independent manner. Co-immunoprecipitation, ubiquitination assay, competition binding assay (SHARPIN vs β-TrCP1), SHARPIN knockdown/overexpression with β-catenin protein stability readout, in vivo xenograft Gastric cancer Medium 33159601
2021 SHARPIN directly interacts with HMGB1 and enhances HMGB1 expression; this SHARPIN-HMGB1 interaction was demonstrated by GST pull-down and Co-IP, and SHARPIN promotes M1-like macrophage polarization via HMGB1. GST pull-down, co-immunoprecipitation, SHARPIN knockdown with HMGB1 overexpression rescue, macrophage polarization assays Metabolic brain disease Low 38805141
2021 SHARPIN promotes ubiquitination and proteasomal degradation of von Hippel-Lindau protein (pVHL) through interaction involving the α and β domains of pVHL and the UBL domain of SHARPIN, leading to sustained HIF-2α activation. Co-immunoprecipitation (domain mapping), ubiquitination assay, pVHL stability assay, SHARPIN knockdown in ccRCC cell lines and xenograft Cancer science Medium 34339558
2022 The N-terminal UBL domain of SHARPIN (residues 1-127) does not participate in LUBAC formation but enhances the structural stability of the central UBL domain (residues 128-309) and strengthens binding of the UBL domain to the HOIP UBA domain. Size exclusion chromatography, circular dichroism, thermal/urea unfolding, biosensor binding assays (N-terminal UBL domain vs central UBL domain constructs) Protein expression and purification Medium 34965468
2022 SHARPIN S146 phosphorylation (induced by ERK1/2 and reversed by PP2A) is required for SHARPIN-ARP2/3 interaction and lamellipodia formation; S146A mutant SHARPIN fails to rescue 3D cancer cell invasion and in vivo metastasis in zebrafish. Mass spectrometry phosphoproteomics, in vitro kinase assay, CRISPR/Cas9 knockout with S146A mutant rescue, 3D invasion assay, zebrafish metastasis model Journal of cell science Medium 36148554
2022 Platelet-specific SHARPIN deletion increases αIIbβ3 colocalization with talin and fibrinogen binding capacity, reduces NF-κB activation and linear ubiquitination upon platelet stimulation, and diminishes inflammation in murine colitis and peritonitis models. Platelet-specific conditional knockout (PF4-Cre, GPIbα-Cre crossed with Sharpin fl/fl), super-resolution microscopy, fibrinogen binding assay, ubiquitination assay, in vivo colitis/peritonitis models Blood advances High 34991155
2022 SHARPIN inhibits ferroptosis in cholangiocarcinoma via the p53/SLC7A11/GPX4 signaling pathway; SHARPIN silencing inhibits p53 ubiquitination and degradation, leading to p53 accumulation and downregulation of SLC7A11, GPX4, SOD-1, and SOD-2. siRNA knockdown and lentiviral overexpression, western blot (p53, SLC7A11, GPX4 levels), ubiquitination assay, ROS measurement, mitochondrial staining Cancer science Low 35968603
2023 HOIL-1L and SHARPIN each form homo-dimers through their LTM (Leu-Thr-Met) motifs; crystal structures of the dimeric LTM motifs of both proteins reveal a shared dimerization mode, and the polyglucosan body myopathy-associated HOIL-1L A18P mutation disrupts LTM structural folding and dimer formation. Crystal structure determination of HOIL-1L and SHARPIN LTM homo-dimers, site-directed mutagenesis (A18P), dimerization assays Biochemical and biophysical research communications High 37976837
2014 SIPL1 (SHARPIN) promotes PTEN polyubiquitination via K63-linked (not K48-linked) polyubiquitin chains using its UBL domain; this ubiquitination promotes SIPL1-PTEN complex formation. Co-immunoprecipitation with ubiquitin mutants (K48R, K63R, K0), UBL domain deletion mutant, ubiquitination assays Cellular signalling Medium 25152374
2017 A rare missense variant in SHARPIN (G186R/rs572750141) causes aberrant cellular localization of the variant protein and attenuated NF-κB activation; molecular dynamics simulations and Co-IP showed significantly reduced binding between G186R SHARPIN and HOIP. Functional complementation assay, NF-κB activation assay in variant-expressing cells, co-immunoprecipitation, molecular dynamics simulation, subcellular localization imaging Molecular medicine Medium 31216982
2024 Human biallelic SHARPIN loss causes attenuated canonical NF-κB responses and propensity for TNF superfamily member-induced cell death in fibroblasts and B cells; anti-TNF therapy led to complete clinical and transcriptomic resolution of autoinflammation in an affected individual. Patient fibroblasts and B cells: NF-κB signaling assays, cell death assays; anti-TNF clinical intervention with transcriptomic resolution Nature immunology High 38609546
2024 SHARPIN NZF domains of both HOIL-1L and SHARPIN synergistically regulate LUBAC function; SHARPIN NZF binds K63-linked ubiquitin chains (in addition to linear chains) and predominantly regulates cell death protection independently of ubiquitin chain type, while HOIL-1L NZF binding to linear chains is required for full NF-κB activation and cooperates in cell death protection. NZF ubiquitin-binding assays, LUBAC function assays (NF-κB activation, cell death protection), compound NZF mutant analysis, small-molecule inhibitor screen Cell death & disease Medium 39528476

Source papers

Stage 0 corpus · 91 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 622 21455181
2011 SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 529 21455180
2014 Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 324 24821972
2014 TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. eLife 236 25443632
2007 Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes and immunity 182 17538631
2011 SHARPIN is an endogenous inhibitor of β1-integrin activation. Nature cell biology 165 21947080
2014 Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. eLife 161 25443631
2001 Sharpin, a novel postsynaptic density protein that directly interacts with the shank family of proteins. Molecular and cellular neurosciences 126 11178875
2022 SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via p53/SLC7A11/GPX4 signaling. Cancer science 112 35968603
2015 The Inflammatory Caspases-1 and -11 Mediate the Pathogenesis of Dermatitis in Sharpin-Deficient Mice. Journal of immunology (Baltimore, Md. : 1950) 64 26216893
2015 SHARPIN overexpression induces tumorigenesis in human prostate cancer LNCaP, DU145 and PC-3 cells via NF-κB/ERK/Akt signaling pathway. Medical oncology (Northwood, London, England) 63 25550157
2011 Systems analysis identifies an essential role for SHANK-associated RH domain-interacting protein (SHARPIN) in macrophage Toll-like receptor 2 (TLR2) responses. Proceedings of the National Academy of Sciences of the United States of America 61 21709223
2012 SHARPIN is a key regulator of immune and inflammatory responses. Journal of cellular and molecular medicine 55 22452937
2010 Newly identified tumor-associated role of human Sharpin. Molecular and cellular biochemistry 55 20179993
2016 SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex. Nature immunology 53 26829767
2015 Cutting edge: SHARPIN is required for optimal NLRP3 inflammasome activation. Journal of immunology (Baltimore, Md. : 1950) 52 25637014
2014 Chronic proliferative dermatitis in Sharpin null mice: development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling. PloS one 48 24465642
2013 SHARPIN regulates uropod detachment in migrating lymphocytes. Cell reports 48 24210817
2010 Inhibition of NF-κB signaling retards eosinophilic dermatitis in SHARPIN-deficient mice. The Journal of investigative dermatology 45 20811394
2014 Activation of nuclear factor κB pathway and downstream targets survivin and livin by SHARPIN contributes to the progression and metastasis of prostate cancer. Cancer 44 24925528
2016 SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland. The EMBO journal 41 27974362
2019 SHARPIN Promotes Melanoma Progression via Rap1 Signaling Pathway. The Journal of investigative dermatology 39 31401046
2017 SHARPIN Facilitates p53 Degradation in Breast Cancer Cells. Neoplasia (New York, N.Y.) 39 28063307
2010 Sipl1 and Rbck1 are novel Eya1-binding proteins with a role in craniofacial development. Molecular and cellular biology 39 20956555
2019 A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer's disease. Molecular medicine (Cambridge, Mass.) 38 31216982
2017 SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth. The Journal of clinical investigation 37 29227283
2011 SHARPIN regulates mitochondria-dependent apoptosis in keratinocytes. Journal of dermatological science 34 21620685
2017 SHARPIN stabilizes estrogen receptor α and promotes breast cancer cell proliferation. Oncotarget 32 29100376
2015 Elevation of SIPL1 (SHARPIN) Increases Breast Cancer Risk. PloS one 32 25992689
2017 A novel SHARPIN-PRMT5-H3R2me1 axis is essential for lung cancer cell invasion. Oncotarget 31 28903384
2012 SHARPIN is essential for cytokine production, NF-κB signaling, and induction of Th1 differentiation by dendritic cells. PloS one 31 22348129
2020 A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer's disease. Neurobiology of aging 30 32165044
2019 SHARPIN Inhibits Esophageal Squamous Cell Carcinoma Progression by Modulating Hippo Signaling. Neoplasia (New York, N.Y.) 29 31884247
2018 Innate immune adaptor MyD88 deficiency prevents skin inflammation in SHARPIN-deficient mice. Cell death and differentiation 27 30038386
2016 Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression. Oncogenesis 27 27941932
2012 Structural analysis of SHARPIN, a subunit of a large multi-protein E3 ubiquitin ligase, reveals a novel dimerization function for the pleckstrin homology superfold. The Journal of biological chemistry 27 22549881
2016 Distinct role of IL-1β in instigating disease in Sharpincpdm mice. Scientific reports 26 27892465
2009 Anti-IL5 decreases the number of eosinophils but not the severity of dermatitis in Sharpin-deficient mice. Experimental dermatology 26 19650867
2012 Sharpin contributes to TNFα dependent NFκB activation and anti-apoptotic signalling in hepatocytes. PloS one 25 22253853
2024 Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency. Nature immunology 24 38609546
2016 An Essential Role for SHARPIN in the Regulation of Caspase 1 Activity in Sepsis. The American journal of pathology 24 26968342
2016 Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection. Molecular and cellular biology 24 26976635
2016 SHARPIN controls the development of regulatory T cells. Immunology 22 26931177
2015 Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-κB Signaling. PloS one 22 26600301
2019 SHARPIN at the nexus of integrin, immune, and inflammatory signaling in human platelets. Proceedings of the National Academy of Sciences of the United States of America 21 30804189
2014 SIPL1-facilitated PTEN ubiquitination contributes to its association with PTEN. Cellular signalling 20 25152374
2021 A missense variant in SHARPIN mediates Alzheimer's disease-specific brain damages. Translational psychiatry 17 34785643
2019 Atypical ubiquitin-binding protein SHARPIN promotes breast cancer progression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 17 31518875
2010 Loss-of-function of SHARPIN causes an osteopenic phenotype in mice. Endocrine 17 21069580
2021 Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death. Proceedings of the National Academy of Sciences of the United States of America 16 34887354
2020 SHARPIN stabilizes β-catenin through a linear ubiquitination-independent manner to support gastric tumorigenesis. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 16 33159601
2017 Lack of interaction between NEMO and SHARPIN impairs linear ubiquitination and NF-κB activation and leads to incontinentia pigmenti. The Journal of allergy and clinical immunology 15 28249776
2020 Imaging genomics discovery of a new risk variant for Alzheimer's disease in the postsynaptic SHARPIN gene. Human brain mapping 14 32558014
2020 Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice. PloS one 14 32687504
2019 Sharpin suppresses β1-integrin activation by complexing with the β1 tail and kindlin-1. Cell communication and signaling : CCS 14 31429758
2017 Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice. PloS one 14 29040328
2017 Reduced SHARPIN and LUBAC Formation May Contribute to CCl₄- or Acetaminophen-Induced Liver Cirrhosis in Mice. International journal of molecular sciences 13 28165393
2013 Loss of function of the mouse Sharpin gene results in Peyer's patch regression. PloS one 12 23424624
2019 68Ga-DOTA-E[c(RGDfK)]2 PET Imaging of SHARPIN-Regulated Integrin Activity in Mice. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 11 30850498
2015 The pathogenesis of chronic eosinophilic esophagitis in SHARPIN-deficient mice. Experimental and molecular pathology 11 26321245
2018 Down-regulated SHARPIN may accelerate the development of atopic dermatitis through activating interleukin-33/ST2 signalling. Experimental dermatology 10 30230040
2017 Elevation of SHARPIN Protein Levels in Prostate Adenocarcinomas Promotes Metastasis and Impairs Patient Survivals. The Prostate 10 28230260
2022 Advances in the Structural and Physiological Functions of SHARPIN. Frontiers in immunology 9 35547743
2021 SHARPIN regulates the development of clear cell renal cell carcinoma by promoting von Hippel-Lindau protein ubiquitination and degradation. Cancer science 9 34339558
2020 Serine 165 phosphorylation of SHARPIN regulates the activation of NF-κB. iScience 9 33392484
2017 The Sharpin interactome reveals a role for Sharpin in lamellipodium formation via the Arp2/3 complex. Journal of cell science 9 28775156
2014 SIPL1 enhances the proliferation, attachment, and migration of CHO cells by inhibiting PTEN function. International journal of molecular medicine 9 25018115
2011 SHARPIN negatively associates with TRAF2-mediated NFκB activation. PloS one 9 21829440
2024 SHARPIN is a novel gene of colorectal cancer that promotes tumor growth potentially via inhibition of p53 expression. International journal of oncology 8 39450547
2022 Platelet SHARPIN regulates platelet adhesion and inflammatory responses through associations with αIIbβ3 and LUBAC. Blood advances 8 34991155
2021 SHARPIN: Role in Finding NEMO and in Amyloid-Beta Clearance and Degradation (ABCD) Pathway in Alzheimer's Disease? Cellular and molecular neurobiology 8 33400084
2017 A role of SIPL1/SHARPIN in promoting resistance to hormone therapy in breast cancer. Biochimica et biophysica acta. Molecular basis of disease 8 29248549
2015 Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells. Journal of immunology (Baltimore, Md. : 1950) 8 26363054
2023 SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction. Cancers 7 37444594
2019 SHARPIN overexpression promotes TAK1 expression and activates JNKs and NF-κB pathway in Mycosis Fungoides. Experimental dermatology 7 31461795
2016 Angiogenesis in the skin of SHARPIN-deficient mice with chronic proliferative dermatitis. Experimental and molecular pathology 7 27794420
2022 Characterization of SHARPIN knockout Syrian hamsters developed using CRISPR/Cas9 system. Animal models and experimental medicine 6 36097701
2014 The alteration of SHARPIN expression in the mouse brainstem during herpes simplex virus 1-induced facial palsy. Neuroscience letters 6 25484257
2022 SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis. Journal of cell science 5 36148554
2020 SHARPIN regulates cell proliferation of cutaneous basal cell carcinoma via inactivation of the transcriptional factors GLI2 and c‑JUN. Molecular medicine reports 5 32319607
2014 Sharpin is a key regulator of skeletal homeostasis in a TNF-dependent manner. Journal of musculoskeletal & neuronal interactions 5 25524971
2019 Aberrant expression and high-frequency mutations of SHARPIN in nonmelanoma skin cancer. Experimental and therapeutic medicine 4 30936956
2021 Biochemical and functional characterization of the N-terminal ubiquitin-like domain of human SHARPIN. Protein expression and purification 2 34965468
2017 Loss of FAS/FASL signalling does not reduce apoptosis in Sharpin null mice. Experimental dermatology 2 28094869
2012 Crystallization of SHARPIN using an automated two-dimensional grid screen for optimization. Acta crystallographica. Section F, Structural biology and crystallization communications 2 22750873
2024 Synergistic involvement of the NZF domains of the LUBAC accessory subunits HOIL-1L and SHARPIN in the regulation of LUBAC function. Cell death & disease 1 39528476
2023 Mechanistic insights into the homo-dimerization of HOIL-1L and SHARPIN. Biochemical and biophysical research communications 1 37976837
2022 Overexpression of SHARPIN promotes tumor progression in ovarian cancer. Experimental and molecular pathology 1 35798064
2013 [Effects of SIPL1 screened by suppression subtractive hybridization (SSH) on biological function and drug resistance of renal cell carcinoma cells]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 1 24506958
2024 SHARPIN contributes to sevoflurane-induced neonatal neurotoxicity through up-regulating HMGB1 to repress M2 like-macrophage polarization. Metabolic brain disease 0 38805141
2023 Mind bomb 2 limits inflammatory dermatitis in Sharpin mutant mice independently of cell death. PNAS nexus 0 38156288

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