IRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS.

ABSTRACT: Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor-? (TNF?), which is shed from the plasma membrane after cleavage by the TNF? convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNF? shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNF? in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.

SUBMITTER: McIlwain DR 

PROVIDER: S-EPMC4250273 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature