Shank-associated RH domain-interacting protein (SHARPIN)

Shank-associated RH domain-interacting protein (SHARPIN) is a multifunctional, 387-amino-acid adapter protein initially identified as a binding partner of SHANK proteins. SHARPIN is a critical component of the linear ubiquitin chain assembly complex (LUBAC), working alongside HOIP and HOIL-1L to catalyze linear (Met1-linked) ubiquitination, primarily affecting key signaling intermediates such as NEMO in the NF-κB pathway[1][3]. Structurally, SHARPIN comprises a pleckstrin homology (PH) domain at its N-terminus, a ubiquitin-like (UBL) domain, and an Npl4 zinc finger (NZF) domain at the C-terminus, enabling interactions with other LUBAC subunits and ubiquitin chains[1][2][5]. SHARPIN orchestrates signal transduction in diverse biological processes, especially in immunity, cell survival, inflammation, and apoptosis. Mutations or deficiency in SHARPIN in animal models cause chronic proliferative dermatitis, multi-organ dysfunction, and immune cell abnormalities. Overexpression or dysregulation has proto-oncogenic roles, promoting tumorigenesis, metastasis, and cancer cell proliferation in several tissue types, and it is implicated in the pathogenesis of Alzheimer’s disease via inflammatory pathways. There are no currently known drugs that directly target SHARPIN, nor validated clinical biomarkers or approved mechanisms of action using pharmacological agents[1][3]. SHARPIN remains a biologically validated target, primarily by genetic and mechanistic studies, and is considered a promising candidate for therapeutic exploration due to its central role in disease-relevant signaling pathways.

Other names

SIPL1PSEC0216hSIPL1DKFZP434N1923Shank-interacting protein-like 1AIFIDsharpinshank-associated RH domain-interacting proteinSHARPIN