Abstract
NFκB is an inducible transcriptional factor controlled by two principal signaling cascades and plays pivotal roles in diverse physiological processes including inflammation, apoptosis, oncogenesis, immunity, and development. Activation of NFκB signaling was detected in skin of SHAPRIN-deficient mice and can be diminished by an NFκB inhibitor. However, in vitro studies demonstrated that SHARPIN activates NFκB signaling by forming a linear ubiquitin chain assembly complex with RNF31 (HOIP) and RBCK1 (HOIL1). The inconsistency between in vivo and in vitro findings about SHARPIN's function on NFκB activation could be partially due to SHARPIN's potential interactions with downstream molecules of NFκB pathway. In this study, 17 anti-flag immunoprecipitated proteins, including TRAF2, were identified by mass spectrum analysis among Sharpin-Flag transfected mouse fibroblasts, B lymphocytes, and BALB/c LN stroma 12 cells suggesting their interaction with SHARPIN. Interaction between SHARPIN and TRAF2 confirmed previous yeast two hybridization reports that SHARPIN was one TRAF2's partners. Furthermore, luciferase-based NFκB reporter assays demonstrated that SHARPIN negatively associates with NFκB activation, which can be partly compensated by over-expression of TRAF2. These data suggested that other than activating NFκB signaling by forming ubiquitin ligase complex with RNF31 and RBCK1, SHARPIN may also negatively associate with NFκB activation via interactions with other NFκB members, such as TRAF2.
Highlights
While the protein, SHAPRIN (SHANK-associated RH domain interacting protein), has been known about for a decade, its role in causing immune disease and inflammation is just becoming appreciated
Activation of NFkB signaling in the skin was identified as the primary cause of the chronic proliferative dermatitis phenotype in Sharpincpdm mutant mice and inhibition of NFkB activation by bortezormib can alleviate the skin phenotype suggesting a treatment for some forms of hypereosinophilic syndrome in humans
The present study identified 17 putative proteins that interact with SHARPIN among which TRAF2 was previously identified in yeast-two hybrid studies
Summary
SHAPRIN (SHANK-associated RH domain interacting protein), has been known about for a decade, its role in causing immune disease and inflammation is just becoming appreciated. Lack of the Sharpin gene and the protein (SHARPIN) leads to TNF-dependent inflammation of organs, the skin, characterized as chronic proliferative dermatitis with keratinocyte death [1,2,3]. Mice deficient in Sharpin develop a severe autoinflammatory disorder with NFkB activation, in the absence of infectious agents, autoantibodies, or antigen-specific autoreactive T-cells [4]. This multiorgan-involved disorder was first described in a spontaneous, autosomal recessive mutation in mice and was named the chronic proliferative dermatitis mutation SHARPIN is an important protein involved with multiple molecular pathways
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