SHARPIN

SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation1,2. More than that, SHARPIN deficiency leads to rapid cell death upon tumor-necrosis factor a (TNF-a) stimulation via FADD and caspase-8-dependent pathways. SHARPIN thus activates NFkB and inhibits apoptosis via distinct pathways in vivo.

SHARPIN

Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation (PubMed:21455173, PubMed:21455180, PubMed:21455181).
LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways (PubMed:21455173, PubMed:21455180, PubMed:21455181).
Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation (PubMed:21455173, PubMed:21455180, PubMed:21455181).
LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex (PubMed:21455173, PubMed:21455180, PubMed:21455181).
The LUBAC complex is also involved in innate immunity by conjugating linear polyubiquitin chains at the surface of bacteria invading the cytosol to form the ubiquitin coat surrounding bacteria (PubMed:28481331).
LUBAC is not able to initiate formation of the bacterial ubiquitin coat, and can only promote formation of linear polyubiquitins on pre-existing ubiquitin (PubMed:28481331).
The bacterial ubiquitin coat acts as an 'eat-me' signal for xenophagy and promotes NF-kappa-B activation (PubMed:28481331).
Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis (PubMed:23708998).

Biological Process apoptotic nuclear changesIEA:Ensembl
Biological Process brain developmentIEA:Ensembl
Biological Process defense response to bacteriumManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process keratinizationIEA:Ensembl
Biological Process mitochondrion organizationIEA:Ensembl
Biological Process negative regulation of inflammatory responseISS:UniProtKB
Biological Process positive regulation of I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process proteasome-mediated ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIBA:GO_Central
Biological Process protein linear polyubiquitinationManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process regulation of CD40 signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process regulation of tumor necrosis factor-mediated signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB

Cytoplasm, cytosol
Synapse
Enriched at synaptic sites in mature neurons where it colocalizes with SHANK1.