Affinage

SHARPIN

Sharpin · UniProt Q9H0F6

Length
387 aa
Mass
39.9 kDa
Annotated
2026-04-28
91 papers in source corpus 37 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHARPIN is a multifunctional adaptor protein that serves as an accessory subunit of the linear ubiquitin chain assembly complex (LUBAC), where it binds HOIP/RNF31 via its ubiquitin-like (UBL) domain and facilitates linear (Met1-linked) ubiquitination of NEMO, thereby activating canonical NF-κB signaling and protecting cells from TNF-induced apoptosis and necroptosis; the inflammatory pathology caused by SHARPIN deficiency is driven by TNFR1 signaling, RIPK1 kinase activity, and the deubiquitinase CYLD, and biallelic SHARPIN loss in humans causes autoinflammation that is fully resolved by anti-TNF therapy (PMID:21455181, PMID:21455180, PMID:24821972, PMID:25443632, PMID:34887354, PMID:38609546). Independent of LUBAC, SHARPIN directly binds integrin α-subunit cytoplasmic tails through its UBL domain — competing with HOIP for the same binding surface — to inhibit integrin activation by blocking talin and kindlin recruitment, a function demonstrated for β1-integrins, β2-integrins (LFA-1), and αIIbβ3 in platelets (PMID:21947080, PMID:24210817, PMID:30804189, PMID:26600301). SHARPIN also acts outside the LUBAC–integrin axis: it inhibits caspase-1 by disrupting p20/p10 dimerization, suppresses proximal TCR signaling via K63-ubiquitin-dependent exclusion of ZAP70 from TCRζ, promotes lamellipodium formation through ERK-dependent S146 phosphorylation and Arp2/3 complex interaction, enhances PRMT5 methyltransferase activity, and modulates the stability of p53 (via MDM2), β-catenin, and pVHL through ubiquitination-dependent mechanisms (PMID:26968342, PMID:26829767, PMID:36148554, PMID:29227283, PMID:28063307, PMID:33159601, PMID:34339558). Biallelic loss-of-function mutations in SHARPIN cause a human autoinflammatory disease characterized by attenuated NF-κB responses and TNF superfamily–driven cell death (PMID:38609546).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    Before SHARPIN's signaling roles were known, its initial identification as a Shank-binding postsynaptic density protein established it as a scaffolding adaptor capable of homomultimerization, setting the stage for understanding its broader interaction repertoire.

    Evidence Yeast two-hybrid and co-immunoprecipitation from brain lysates with domain mapping

    PMID:11178875

    Open questions at the time
    • Functional significance of SHARPIN at excitatory synapses remains undefined
    • Whether synaptic SHARPIN affects Shank-dependent signaling is untested
  2. 2010 Medium

    Before LUBAC function was linked to SHARPIN, its interaction with Eya1 and enhancement of Six-dependent transcription revealed a role in developmental transcriptional coactivation, broadening the protein's functional scope beyond scaffolding.

    Evidence GST pulldown, coactivator assay, zebrafish morpholino knockdown producing BOR-like phenotype

    PMID:20956555

    Open questions at the time
    • The mammalian developmental relevance of the SHARPIN–Eya1 axis is not confirmed by knockout
    • Whether this function is LUBAC-dependent is unknown
  3. 2011 High

    The central mechanistic advance was the simultaneous discovery by two groups that SHARPIN is a bona fide LUBAC subunit: it binds HOIP, stimulates linear ubiquitin chain formation on NEMO, activates NF-κB, and protects cells from TNF-induced apoptosis, explaining the chronic proliferative dermatitis (cpdm) mouse phenotype.

    Evidence Co-immunoprecipitation, in vitro ubiquitination, cpdm mouse genetic model, MEF and B cell assays (two independent Nature papers)

    PMID:21455180 PMID:21455181 PMID:21709223

    Open questions at the time
    • Structural basis of SHARPIN–HOIP interaction at atomic resolution was not yet defined
    • Relative contributions of SHARPIN versus HOIL-1L NZF domains to LUBAC recruitment were unclear
  4. 2011 High

    In parallel with the LUBAC discovery, SHARPIN was found to directly bind integrin α-subunit cytoplasmic tails and inhibit β1-integrin activation by preventing talin and kindlin recruitment, establishing a LUBAC-independent function.

    Evidence RNAi screen, direct binding assay, rescue in SHARPIN-deficient fibroblasts/leukocytes/keratinocytes

    PMID:21947080

    Open questions at the time
    • Whether integrin inhibition contributes to the cpdm phenotype was not separated from NF-κB defects
    • Structural mechanism of α-tail binding was not resolved
  5. 2012 High

    Crystallography of the N-terminal domain revealed a PH superfold that functions as a dimerization module rather than a ligand-binding domain, providing structural basis for SHARPIN self-association.

    Evidence Crystal structure of N-terminal SHARPIN fragment with functional dimerization validation

    PMID:22549881

    Open questions at the time
    • How dimerization affects LUBAC assembly or integrin inhibition was not tested
    • Full-length SHARPIN structure remained unavailable
  6. 2014 High

    Genetic epistasis experiments resolved the cell death pathways downstream of SHARPIN loss: TNFR1 (not TNFR2) is the primary driver, RIPK1 kinase activity is essential, and both apoptosis (via TRADD/FADD in keratinocytes) and necroptosis contribute tissue-specifically to the cpdm phenotype.

    Evidence Intercross of cpdm mice with Ripk1(K45A), Tnfr1-KO, Tnfr2-KO, Ripk3-KO, Casp8-het, tissue-specific FADD deletion

    PMID:24821972 PMID:25443631 PMID:25443632

    Open questions at the time
    • Which LUBAC substrates beyond NEMO are critical for cell death protection was not defined
    • Non-TNF cytokine contributions were not fully excluded
  7. 2015 High

    Binding competition experiments showed that the integrin α-tail and HOIP bind the same UBL domain surface on SHARPIN, making integrin inhibition and LUBAC activation mutually exclusive — revealing a molecular switch governing SHARPIN's dual functions.

    Evidence In vitro competition binding assay, V267/L276 mutagenesis, NF-κB reporter assay

    PMID:26600301

    Open questions at the time
    • How the switch is regulated in vivo (post-translational modifications, localization) is unknown
    • Whether the competition is relevant in all cell types is untested
  8. 2016 High

    SHARPIN was shown to have LUBAC-independent roles in immune regulation: it inhibits caspase-1 by disrupting p20/p10 dimerization, and its K63-ubiquitin conjugation suppresses TCRζ–ZAP70 association, affecting regulatory T cell generation.

    Evidence Co-immunoprecipitation with dimerization assay and genetic validation (caspase-1); co-IP with K63-Ub and Treg transfer rescue (TCR signaling)

    PMID:26829767 PMID:26968342

    Open questions at the time
    • The E3 ligase catalyzing K63-ubiquitination of SHARPIN in T cells is unidentified
    • Whether caspase-1 inhibition is relevant in vivo beyond the sepsis model is unclear
  9. 2016 High

    The SHARPIN NZF domain was shown to be specifically required for LUBAC recruitment to the TNFR complex via K63-linked ubiquitin binding, distinguishing it functionally from the HOIL-1L NZF domain.

    Evidence NZF mutagenesis, TNFR complex recruitment assay, HOIL-1L/SHARPIN double KO intercross

    PMID:26976635

    Open questions at the time
    • Whether NZF-mediated recruitment is regulated by post-translational modifications is unknown
  10. 2017 High

    SHARPIN was found to interact with the Arp2/3 complex in a LUBAC-independent manner to promote lamellipodium formation, and separately to enhance PRMT5 methyltransferase activity controlling SOX10/MITF expression and metastasis-related gene transcription, expanding its roles to cytoskeletal dynamics and epigenetic regulation.

    Evidence Mass spectrometry interactome, Arp2/3-binding-deficient mutant (lamellipodium); co-IP with in vitro methyltransferase and ChIP assays (PRMT5)

    PMID:28775156 PMID:28903384 PMID:29227283

    Open questions at the time
    • The kinase phosphorylating S146 to regulate Arp2/3 binding was not yet identified
    • Whether PRMT5 activation by SHARPIN occurs in non-cancer contexts is untested
  11. 2017 Medium

    Multiple studies established SHARPIN as a regulator of protein stability through ubiquitination-dependent mechanisms: it promotes MDM2-dependent p53 degradation and stabilizes ERα by switching its ubiquitination from poly- to mono-ubiquitination.

    Evidence Co-immunoprecipitation, ubiquitination assays, protein stability assays in breast cancer cells

    PMID:28063307 PMID:29100376

    Open questions at the time
    • Whether SHARPIN acts as a direct E3 ligase or purely as an adaptor for these substrates is unresolved
    • Single-lab findings for each substrate
  12. 2019 High

    Platelet-specific studies confirmed SHARPIN's dual function in an important physiological context: it inhibits αIIbβ3-integrin activation (increasing talin–integrin colocalization upon deletion) and supports LUBAC-dependent linear ubiquitination and NF-κB activation in platelets.

    Evidence Platelet-specific conditional KO (PF4-Cre, GPIbα-Cre), super-resolution microscopy, flow cytometry, in vivo inflammation models

    PMID:30804189 PMID:34991155

    Open questions at the time
    • Whether platelet SHARPIN loss affects thrombosis risk in vivo needs further study
    • The relative importance of integrin versus NF-κB functions in platelet biology is not separated
  13. 2021 High

    The full cpdm phenotype was shown to require the deubiquitinase CYLD: SHARPIN loss impairs IKK-mediated CYLD phosphorylation at S418, unleashing CYLD activity that deubiquitinates RIPK1 and promotes its recruitment to death-inducing Complex II.

    Evidence Sharpin/Cyld double KO, tissue-specific Cyld deletion, RIPK1 Complex II immunoprecipitation, CYLD phosphorylation analysis

    PMID:34887354

    Open questions at the time
    • Whether CYLD directly deubiquitinates linear chains on NEMO or acts on other substrates is not resolved
    • Whether pharmacological CYLD inhibition could be therapeutic is untested
  14. 2022 High

    ERK1/2-dependent phosphorylation of SHARPIN at S146 was identified as the signal controlling Arp2/3 interaction, lamellipodia formation, and cancer cell invasion/metastasis, revealing a phospho-switch for SHARPIN's cytoskeletal function.

    Evidence In vitro kinase assay, mass spectrometry, CRISPR KO with S146A mutant rescue, zebrafish metastasis model

    PMID:36148554

    Open questions at the time
    • The PP2A holoenzyme subunit targeting pS146 is not identified
    • Whether S146 phosphorylation affects other SHARPIN functions is unknown
  15. 2023 High

    Crystal structures of SHARPIN LTM motif dimers revealed the molecular basis for LUBAC subunit homo- and hetero-dimerization, and linked a disease-associated HOIL-1L mutation (A18P) to disrupted dimer formation.

    Evidence Crystal structure determination of LTM dimers with disease mutation structural analysis

    PMID:37976837

    Open questions at the time
    • Full LUBAC holocomplex structure is still unavailable
    • How LTM dimerization regulates catalytic activity quantitatively is not defined
  16. 2024 High

    Biallelic SHARPIN loss was identified in human patients with autoinflammation, confirming the mouse-to-human translational relevance: patient cells show attenuated NF-κB and TNF-driven cell death, and anti-TNF therapy fully resolved disease, establishing SHARPIN deficiency as a human Mendelian autoinflammatory condition.

    Evidence Patient-derived fibroblast and B cell functional assays, NF-κB signaling, anti-TNF treatment with transcriptomic validation

    PMID:38609546

    Open questions at the time
    • The full clinical spectrum of human SHARPIN deficiency beyond autoinflammation is not characterized
    • Whether integrin dysregulation contributes to the human phenotype is unknown
  17. 2024 High

    Cooperative regulation by HOIL-1L and SHARPIN NZF domains was demonstrated: HOIL-1L NZF preferentially binds linear chains while SHARPIN NZF binds both K63 and linear chains, and simultaneous loss profoundly impairs NF-κB and cell death protection, refining the model of accessory subunit function within LUBAC.

    Evidence NZF domain mutagenesis, ubiquitin chain-binding assays, NF-κB and cell death functional assays

    PMID:39528476

    Open questions at the time
    • How NZF ubiquitin-type selectivity is determined structurally is unresolved
    • Whether NZF functions can be pharmacologically targeted is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length atomic structure of SHARPIN, the in vivo regulatory logic governing the UBL domain switch between HOIP and integrin binding, whether SHARPIN's LUBAC-independent functions (caspase-1 inhibition, PRMT5 activation, Arp2/3 interaction) are interdependent or independently regulated, and the complete clinical spectrum of human SHARPIN deficiency.
  • Full-length SHARPIN structure not available
  • In vivo regulation of the HOIP–integrin binding switch is undefined
  • Interplay among LUBAC-independent functions is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 5 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 6 R-HSA-168256 Immune System 5 R-HSA-1500931 Cell-Cell communication 4 R-HSA-162582 Signal Transduction 4
Partners
ACTR2CASP1CYLDIKBKGPRMT5RBCK1RNF31SHANK1
Complex memberships
LUBAC

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) by binding to the LUBAC subunit HOIP (RNF31), thereby stimulating the formation of linear ubiquitin chains in vitro and in vivo, promoting linear ubiquitination of NEMO and subsequent NF-κB activation, and protecting against TNF-α-induced apoptosis via FADD- and caspase-8-dependent pathways. Co-immunoprecipitation, in vitro ubiquitination assay, genetic KO (cpdm mice), MEF and B cell functional assays Nature High 21455180 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, thereby preventing the switch from inactive to active integrin conformations. RNAi screen, direct binding assay, rescue experiments in SHARPIN-deficient fibroblasts/leukocytes/keratinocytes, re-expression of SHARPIN Nature cell biology High 21947080
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 mediates Shank interaction while the N-terminal half mediates SHARPIN homomultimerization. Yeast two-hybrid, co-immunoprecipitation in heterologous cells and brain, immunostaining Molecular and cellular neurosciences High 11178875
2012 The N-terminal portion of SHARPIN adopts a pleckstrin homology (PH) superfold that acts as a dimerization module rather than a canonical ligand-recognition domain, extending the functional applications of this structural fold. Crystal structure determination of N-terminal SHARPIN fragment The Journal of biological chemistry High 22549881
2014 RIPK1 kinase activity is required for the inflammatory pathology in SHARPIN-deficient (cpdm) mice; crossing with kinase-dead Ripk1(K45A) mice fully protected against all cpdm-related pathology, placing RIPK1 kinase activity downstream of SHARPIN in TNF-driven inflammatory cell death. Genetic epistasis — Ripk1(K45A) knockin crossed with Sharpincpdm mice, in vitro and in vivo necroptosis assays Journal of immunology High 24821972
2014 TNFR1 (but not TNFR2) signaling is the primary driver of multi-organ inflammation in Sharpin-deficient mice; RIPK3 deficiency combined with Caspase-8 heterozygosity almost completely suppressed the phenotype, placing necroptosis and apoptosis downstream of TNFR1 in SHARPIN-deficient inflammation. Genetic epistasis — Tnfr1/Tnfr2/Ripk3/Casp8/Mlkl deletions crossed with Sharpincpdm mice eLife High 25443632
2014 TRADD- and FADD-dependent keratinocyte apoptosis (not necroptosis) is the primary driver of skin inflammation in Sharpin-deficient mice; epidermis-restricted ablation of FADD combined with RIPK3 deficiency fully prevented skin inflammation. Genetic epistasis — tissue-specific KO (Krt14-Cre), FADD/RIPK3 double KO, primary keratinocyte apoptosis assays eLife High 25443631
2011 SHARPIN interacts with NEMO (confirmed by co-immunoprecipitation) and regulates NEMO-dependent signaling including p105 and ERK phosphorylation and p65 nuclear localization in a manner similar to the hypomorphic panr2 NEMO mutation, identifying SHARPIN as an essential adaptor in TLR2-induced NF-κB signaling in macrophages. Systems biology analysis, co-immunoprecipitation, transcriptomic analysis of cpdm macrophages Proceedings of the National Academy of Sciences of the United States of America High 21709223
2013 SHARPIN localizes to the trailing edges (uropods) of chemokine-activated migrating lymphocytes, directly interacts with LFA-1 (lymphocyte-function-associated antigen-1), and inhibits intermediate and high-affinity forms of LFA-1, thereby regulating uropod detachment and migration velocity. Live cell imaging, direct binding assay, SHARPIN-deficient lymphocyte functional assays, rescue by re-expression Cell reports High 24210817
2016 SHARPIN conjugated with K63-linked ubiquitin chains inhibits the association of TCRζ with the signaling kinase Zap70, affecting generation of regulatory T cells; SHARPIN deficiency results in enhanced proximal TCR signaling without affecting NF-κB activation. Co-immunoprecipitation, Treg transfer rescue experiments in SHARPIN-deficient mice, signaling assays Nature immunology High 26829767
2016 SHARPIN directly binds caspase-1 and disrupts p20/p10 dimer formation (the last step of caspase-1 processing), thereby inhibiting caspase-1 enzyme activation and maturation of IL-1β/IL-18 in a LUBAC-independent manner. Co-immunoprecipitation, biochemical dimerization assay, genetic KO (Casp1/Casp11 deletion in Sharpin-deficient background), in vivo sepsis model The American journal of pathology High 26968342
2015 SHARPIN is required for optimal NLRP3 inflammasome activation by both canonical and non-canonical stimuli, and SHARPIN-deficient macrophages show dramatic defects in NF-κB and MAPK pathway activation, suggesting SHARPIN acts in transcriptional priming of NLRP3. Inflammasome activation assays in Sharpincpdm macrophages, IL-1β/caspase-1 cleavage assays Journal of immunology Medium 25637014
2015 SHARPIN's integrin inhibition function and its LUBAC-activating function are mutually exclusive; the integrin α-subunit tail competes with RNF31 (HOIP) for binding to the same ubiquitin-like (UBL) domain of SHARPIN, with two residues (V267, L276) required for both interactions. Domain mapping, in vitro competition binding assay, site-directed mutagenesis, NF-κB reporter assay PloS one High 26600301
2016 The NZF domain of SHARPIN (but not HOIL-1L) is critical for protection from programmed cell death by enhancing recruitment of LUBAC to the activated TNFR complex; this function depends on the SHARPIN NZF domain's ability to bind K63-linked ubiquitin chains. Intercrossing of HOIL-1L and SHARPIN KO mice, domain mutagenesis, TNFR complex recruitment assays Molecular and cellular biology High 26976635
2017 SHARPIN interacts with PRMT5 in a LUBAC-independent manner and increases PRMT5 multiprotein complex assembly and methyltransferase activity; activated PRMT5 controls expression of SOX10 and MITF transcription factors by arginine dimethylation and inhibition of the transcriptional corepressor SKI. Co-immunoprecipitation, in vitro methyltransferase activity assay, arginine dimethylation analysis, genetic rescue The Journal of clinical investigation High 29227283
2017 SHARPIN facilitates p53 poly-ubiquitination and degradation in an MDM2-dependent manner; SHARPIN associates with MDM2 (by co-immunoprecipitation) and prolongs MDM2 protein stability, thereby reducing p53 protein levels and target gene expression in breast cancer cells. Co-immunoprecipitation, ubiquitination assay, protein stability assay, RNA-seq, siRNA knockdown Neoplasia Medium 28063307
2017 SHARPIN stabilizes estrogen receptor α (ERα) by inhibiting ERα poly-ubiquitination while facilitating mono-ubiquitination at K302/303 sites; SHARPIN localizes in the cytosol and interacts with ERα in both cytosol and nucleus, promoting ERα-dependent transcription and breast cancer cell proliferation. Co-immunoprecipitation, ubiquitination assay, luciferase reporter, site-directed mutagenesis, siRNA knockdown Oncotarget Medium 29100376
2017 SHARPIN interacts with PRMT5 to promote monomethylation of histone H3 at arginine 2 (H3R2me1) at metastasis-related gene loci, linking this mark to H3K4me3 via an MLL complex (ASH2/WDR5) to activate metastasis-related gene expression in lung cancer cells. Co-immunoprecipitation, histone methylation assay, chromatin immunoprecipitation Oncotarget Medium 28903384
2016 SHARPIN regulates mammary ductal outgrowth in a stromal-cell-intrinsic manner; SHARPIN-deficient stromal fibroblasts display defects in collagen fibre assembly, contraction, and degradation, leading to reduced ECM stiffness adjacent to invading ducts. Cell-type-specific KO (S100a4-Cre), mammary epithelial transplantation, collagen contraction/degradation in vitro assays The EMBO journal High 27974362
2014 SIPL1 (SHARPIN) promotes PTEN polyubiquitination via K63-linked polyubiquitin chains using its ubiquitin-like (UBL) domain; this ubiquitination promotes and stabilizes the SIPL1/PTEN complex. Ubiquitination assay with ubiquitin K48R and K63R mutants, co-immunoprecipitation, UBL domain mutagenesis Cellular signalling Medium 25152374
2017 SHARPIN interacts with the Arp2/3 complex and promotes lamellipodium formation in a LUBAC-independent manner; the Arp2/3-binding site on SHARPIN was mapped and an Arp2/3-binding-deficient mutant abrogated lamellipodium formation. Mass spectrometry interactome (Sharpin interactome), co-immunoprecipitation, domain mapping, Arp2/3-binding-deficient mutant rescue assay Journal of cell science High 28775156
2020 SHARPIN serine 165 (S165) phosphorylation is constitutively present in lymphoblastoid cells and is further induced by TCR stimulation; a phosphorylation-resistant SHARPIN S165A mutant shows impaired linear ubiquitination of NEMO and reduced NF-κB activation in response to TNFα. Mass spectrometry phosphorylation analysis, phosphorylation-resistant mutant, NF-κB reporter assay, linear ubiquitination assay iScience Medium 33392484
2022 SHARPIN S146 phosphorylation (sensitive to ERK1/2 inhibition and PP2A reactivation) mediates ARP2/3 complex interaction and lamellipodia formation, and is required for 3D cancer cell invasion and in vivo metastasis; S146A mutant SHARPIN fails to rescue invasion in SHARPIN-KO cancer cells. Mass spectrometry, in vitro kinase assay, CRISPR/Cas9 KO, S146A mutant rescue, zebrafish metastasis model Journal of cell science High 36148554
2021 SHARPIN-deficient mouse phenotype (dermatitis, disrupted splenic architecture, loss of Peyer's patches) is fully dependent on CYLD deubiquitinase; absence of SHARPIN impairs CYLD phosphorylation at serine 418 (which normally inhibits CYLD), leading to enhanced RIPK1 recruitment to death-signaling Complex II following TNF stimulation. Genetic epistasis (Sharpin/Cyld double KO), conditional Cyld deletion (LysM-Cre, Cx3cr1-Cre), RIPK1 complex II immunoprecipitation, CYLD phosphorylation analysis Proceedings of the National Academy of Sciences of the United States of America High 34887354
2019 SHARPIN interacts with integrin αIIb in human platelets (pull-down and co-immunoprecipitation) and co-immunoprecipitates with HOIP and HOIL-1 (LUBAC components); SHARPIN knockdown in megakaryocytes/platelets increases αIIbβ3-fibrinogen binding and reduces Met1 linear ubiquitination and NF-κB (RelA) activation. Pull-down, co-immunoprecipitation, SHARPIN knockdown in iPSC-derived megakaryocytes/platelets, flow cytometry, linear ubiquitination assay Proceedings of the National Academy of Sciences of the United States of America High 30804189
2019 SHARPIN suppresses β1-integrin activation by complexing with both the integrin β1 cytoplasmic tail and kindlin-1; kindlin-1 enhances the SHARPIN–β1 tail interaction, and the complex restricts talin head domain binding to the β1 tail. Biochemical binding assays, co-immunoprecipitation, talin competition assay in CHO cells Cell communication and signaling Medium 31429758
2020 SHARPIN stabilizes β-catenin by competing with the E3 ubiquitin ligase β-TrCP1 for β-catenin binding, thereby decreasing β-catenin ubiquitination and preventing its proteasomal degradation in a linear ubiquitination-independent manner. Co-immunoprecipitation, ubiquitination assay, competition binding assay, in vitro and in vivo functional assays Gastric cancer Medium 33159601
2021 SHARPIN promotes ubiquitination and proteasomal degradation of von Hippel-Lindau protein (pVHL) using its ubiquitin-like domain; SHARPIN interaction requires the α and β domains of pVHL, and this leads to sustained HIF-2α activation in clear cell renal cell carcinoma. Co-immunoprecipitation with domain mapping, ubiquitination assay, siRNA knockdown, xenograft model Cancer science Medium 34339558
2019 SHARPIN interacts with YAP protein and promotes YAP K48-linked poly-ubiquitination and degradation, thereby inhibiting YAP/TEAD target gene expression (CTGF, CYR61) and functioning as an endogenous inhibitor of YAP in esophageal squamous cell carcinoma. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, rescue experiment Neoplasia Medium 31884247
2011 SHARPIN deficiency in keratinocytes triggers mitochondria-dependent (intrinsic) apoptosis characterized by mitochondrial membrane depolarization, shift in BCL2/BAX ratio, and activation of caspases 9 and 3 (but not 8), without involvement of the extrinsic caspase-8 pathway. FACS (Annexin V/PI), transmission electron microscopy, caspase activity assays, Western blot for BCL2/BAX Journal of dermatological science Medium 21620685
2023 HOIL-1L and SHARPIN form homo-dimers through their LTM motifs; crystal structures of the dimeric LTM motifs reveal the molecular mechanism of dimerization and a shared mode for homo- and hetero-dimer formation; the polyglucosan body myopathy-associated HOIL-1L A18P mutation disrupts HOIL-1L LTM structural folding and dimer formation. Crystal structure determination of LTM motif dimers, disease mutation analysis, biochemical validation Biochemical and biophysical research communications High 37976837
2024 The NZF domains of HOIL-1L and SHARPIN cooperatively regulate LUBAC function; HOIL-1L NZF preferentially binds linear ubiquitin chains while SHARPIN NZF binds K63-linked chains in addition to linear chains; simultaneous loss of both NZF ubiquitin-binding activities profoundly impairs NF-κB activation and cell death protection. NZF domain mutagenesis, ubiquitin chain-binding assays, NF-κB activation assays, cell death protection assays, compound screen Cell death & disease High 39528476
2024 Biallelic SHARPIN loss in humans causes attenuated canonical NF-κB responses and propensity for cell death mediated by TNF superfamily members in fibroblasts and B cells; anti-TNF therapy completely resolved autoinflammation, confirming TNF-driven pathology. Patient-derived fibroblast and B cell assays, NF-κB signaling assays, anti-TNF treatment with transcriptomic resolution Nature immunology High 38609546
2021 SHARPIN directly interacted with HMGB1 (demonstrated by GST pull-down and co-immunoprecipitation) and enhanced HMGB1 expression, promoting M1-like macrophage polarization and neuroinflammation in sevoflurane-induced neurotoxicity. GST pull-down, co-immunoprecipitation, SHARPIN siRNA knockdown, macrophage polarization assays Metabolic brain disease Low 38805141
2010 SHARPIN was identified as a novel interaction partner of Eya1 (Eyes Absent 1); SHARPIN (as Sipl1) and Rbck1 enhance the function of Eya proteins as coactivators for Six transcription factors, and morpholino knockdown of a Sipl1 ortholog in zebrafish produces a BOR syndrome-like phenotype with ear and branchial arch defects. GST pulldown, co-immunoprecipitation, coactivator transcriptional assay, zebrafish morpholino knockdown Molecular and cellular biology Medium 20956555
2019 Platelet-specific deletion of SHARPIN results in increased colocalization of αIIbβ3 with talin (by super-resolution microscopy), increased fibrinogen binding in response to ADP, and reduced NF-κB activation and linear ubiquitination of substrates; SHARPIN-null platelets show reduced inflammation in colitis and peritonitis models. Platelet-specific conditional KO (PF4-Cre/GPIbα-Cre), super-resolution microscopy, flow cytometry, in vivo inflammation models Blood advances High 34991155

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 616 21455181
2011 SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 527 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) 323 24821972
2014 TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. eLife 234 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 160 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 111 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 40 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 36 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
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
2024 Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency. Nature immunology 23 38609546
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
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
2024 SHARPIN is a novel gene of colorectal cancer that promotes tumor growth potentially via inhibition of p53 expression. International journal of oncology 6 39450547
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