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

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 SHduanyu37IN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHduanyu37IN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHduanyu37IN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHduanyu37IN 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 SHduanyu37IN 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, SHduanyu37IN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHduanyu37IN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.

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