MRC National Institute for Medical Research, London
Science for Health
SHARPIN – a novel component of a linear ubiquitin ligase complex
05 April 2011
NIMR scientists have helped to demonstrate that SHARPIN, a protein whose mutation in mice leads to immune disorders and inflammation, is a novel component of a complex that synthesizes linear ubiquitin chains and regulates NF-κB and apoptotic pathways. The research is published in Nature.
Linear (or M1-linked) ubiquitin chains recently emerged as essential regulators of the NF-κB pathway, controlling immune responses, as well as cell survival and proliferation. Linear ubiquitin chain synthesis relies on two proteins called HOIL-1L and HOIP, which together form the E3 ligase complex called LUBAC (linear ubiquitin chain assembly complex). SHARPIN shares significant sequence homology with the N-terminal region of HOIL-1L, suggesting that it may also play a role in inflammatory and immune processes.
Katrin Rittinger (pictured), from NIMR’s Division of Molecular Structure, has worked with the group of Ivan Dikic in Germany to show that SHARPIN functions as a novel component of LUBAC and that the absence of SHARPIN causes disregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis mutant (cpdm) mice. By directly interacting with the LUBAC subunit HOIP, SHARPIN is able to catalyze the formation of linear ubiquitin chains in vitro and in vivo. Co-expression of SHARPIN and HOIP in HEK293T cells stimulates NF-κB signalling, whereas cells derived from cpdm mice exhibit an impaired activation of NF- κB in response to a number of stimuli. In addition, TNFα induces apoptosis in Sharpincpdm/Sharpincpdm MEFs via FADD- and caspase-8-dependent pathways, which is different from the phenotype observed in fibroblasts lacking HOIL-1L.
Similar findings have been made in two independent parallel studies and together they provide further evidence for the importance of linear ubiquitylation in the regulation of NF-κB and apoptotic pathways in vivo.
This study provides evidence for the existence of multiple distinct LUBAC complexes with overlapping and unique functions. While both HOIL-1L and SHARPIN are accessory partners of HOIP and mediate NF-κB activation downstream of several physiological stimuli, SHARPIN, but not HOIL-1L, deficiency in mice results in increased caspase-dependent apoptosis in mouse embryonic fibroblasts and inflammatory skin lesions. This study exposes a putative role for linear ubiquitylation in the regulation of cell death and reinforces its impact on NF-κB signalling and immune responses. The challenge now is to provide a detailed description of how this enzyme complex functions on a molecular level.
Katrin Rittinger
Original article
SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis
Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJL, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B and Dikic I (2011)
Nature 471:637-41 PubMed abstract
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