iRhom2 regulates specific activation and trafficking of TACE and enhances the survival of TNF α mediated septic shock after LPS treatment

Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. TNFα is a powerful inflammatory cytokines, which controls infection and also acts as a key mediator of septic shock. TNFα which is synthesized as a membrane- bound precursor, is liberated from the cell surface by the TNFα converting enzyme (TACE, also known as ADAM17). We report that the inactive rhomboid family member iRhom2 interact with TACE and regulate TNFα shedding. Based on the results from an unbiased genetic screen, expression of either iRhom1 or iRhom2 lacking part of their extended N-terminal cytoplasmic domain plays important role in the specific activation of ADAM17 and confers resistance to TNF induced cell death via shedding of cell surface TNF receptor. In addition, iRhom2 was found to be critical for TACE maturation and trafficking to the cell surface. Gene-targeted iRhom2-deficient mice conformed that enhanced survial of TNFα induced septic shock after lipopolysaccharide (LPS) treatment. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.

Corresponding author: Lang, Philipp A

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