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Endocr J. 2012;59(8):641-52. Epub 2012 May 19.

Linear ubiquitination: a novel NF-κB regulatory mechanism for inflammatory and immune responses by the LUBAC ubiquitin ligase complex.

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Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.


The NF-κB pathway is a central signaling pathway for inflammatory and immune responses, and aberrant NF-κB signaling is implicated multiple disorders, such as cancer and autoimmune, chronic inflammatory and metabolic diseases. NF-κB is regulated by various post-translational modifications, including phosphorylation and multiple ubiquitinations. We determined that LUBAC (linear ubiquitin chain assembly complex), composed of SHARPIN, HOIL-IL and HOIP, generates a novel type of Met1-linked linear polyubiquitin chain and specifically regulates the canonical NF-κB pathway via the linear ubiquitination of NEMO and RIP1. In the absence of LUBAC components, NF-κB signaling was attenuated and induced apoptosis and inflammation. Many studies on the pathophysiological functions of LUBAC, such as in B cell development, innate immune response, carcinogenesis, and osteogenesis, have been performed recently. This review summarizes these new findings on LUBAC- and linear ubiquitination-mediated NF-κB regulation and their implications in disorders.

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