SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis

By Fumiyo Ikeda, Y. L. Deribe, Sigrid S. Skånland, B. Stieglitz, C. Grabbe, M. Franz-Wachtel, Sjoerd J. L. van Wijk, P. Goswami, V. Nagy, J. Terzic and 10 more. Nature, 2011

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SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/23647681dede0825ada339a7c9c882d033292a45

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Citations in the corpus

Deubiquitylating enzymes and drug discovery: emerging opportunities (2017, background): “Genetic loss of LUBAC components leads to immunodeficiency 174 and inflammatory phenotypes in mice [175] [176] [177] [178] , and mutations in LUBAC components also cause inflammatory conditions in humans 179, 180 .”
Targeting IAP proteins for therapeutic intervention in cancer (2012, background): “In coordination with haem-oxidized IRP2 ubiquitin ligase 1 (HOIL1; also known as RBCK1) and Sharpin, HOIP promotes the assembly of linear ubiquitin chains on NEMO and RIP1, and stabilizes the signalling complexe”
Signaling in innate immunity and inflammation. (2012, background): “Recruitment of LUBAC components sharpin, HOIL-1, and HOIP to the TNF-RI complex is linked to cIAP ubiquitin ligase activity, and linear ubiquitylation of RIP1 and NEMO may stabilize the TNF-RI signaling complex (Haas et al. 2009; Gerlach et al. 2011; Ikeda et al. 2011; Tokunaga et al. 2011).”
ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis) (2019, background): “Similarly, genetic deficiency of the NF-κB and MAPK components suggests a role for the necrosome components RIPK1 and RIPK3 in promoting NLRP3 inflammasome activation, triggering multiple forms of cell death and the development of inflammatory diseases (Ikeda et al., 2011; Matmati et al., 2011; Toku”