Two papers in Nature describe the role of the protein Sharpin (SHANK-associated RH domain interacting protein) in the inflammatory process triggered by the linear ubiquitin ligase complex (LUBAC). In addition, research in mice by the teams in Japan, Germany, and the U.S., demonstrated that lack of sharpin leads to TNF-dependent inflammation of organs, and particularly the skin, characterized as chronic proliferative dermatitis with keratinocyte death. The research team led by Ivan Dikic, Ph.D., from Goethe University in Frankfurt, Germany, suggests that chronic proliferative dermatitis may in some cases result from mutations in a region of LUBAC, a feature that could lead to new approaches to targeted therapeutics for patients with relevant mutations.
Dr. Dikic and colleagues report their research in a paper titled, “SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis.” The second Nature paper, by Osaka University in Japan’s Fuminori Tokunaga, Tomoko Nakagawa, is titled, “Sharpin is a component of the NF-κB-activating linear ubiquitin chain assembly complex.” Drs. Tokunaga and Nakagawa are also co-authors of the paper led by Dr. Dikic.
Dr. Dikic and colleagues report that Sharpin is a ubiquitin-binding and ubiquitin-like-domain containing protein that, when mutated in mice, results in immune system disorders and multiorgan inflammation. Their work has implicated Sharpin as a novel component of LUBAC, and suggests that a lack of Sharpin essentially causes dysregulation of NF-κB and apoptotic signaling pathways. The authors suggest this in turn explains the severe phenotypes displayed by chronic proliferative dermatitis (CPDM) in Sharpin-deficient mice.
The research has shown that Sharpin binds to the LUBAC subunit HOIP (also known as RNF31), and stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of Sharpin and HOIP essentially promotes the linear ubiquitination of NEMO (also known as IKBKG), which is an an adaptor of IkB kinases (IKKs) and activates NF-κB signaling, the authors write. In contrast, Sharpin deficiency in mice impairs activation of the IKK complex and NF-κB in B cells, macrophages, and mouse embryonic fibroblasts. In addition, Sharpin deficiency was found to lead to rapid cell death upon tumor-necrosis factor α (TNF-α) stimulation via FADD and caspase-8-dependent pathways.
The Japanese team’s paper similarly identifies Sharpin as an additional component of LUBAC and reports that Sharpin-containing complexes can linearly ubiquitinate NEMO and activated NF-κB. The research confirmed that deleting Sharpin drastically reduced the amount of LUBAC, resulting in attenuated TNF-α and CD40-mediated activation of NF-kB in mouse embryonic fibroblasts or B cells from CPDM mice. They further suggest that given the pleomorphic phenotype of CPDM mice1, linear polyubiquitination by LUBAC may be involved in several disorders including chronic dermatitis and immunodeficiency. “Enhanced expression of Sharpin has been reported in various human cancers,” the authors note. “Enhanced expression of LUBAC increases NF-κB activation, indicating that overexpression of LUBAC may be involved in tumorigenesis through activation of the anti-apoptotic function of NF-κB.”