Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling

Abstract

Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS) to mount innate immune responses. The TLR4-induced release of pro- and anti-inflammatory cytokines generates robust inflammatory responses, which must then be restrained to avoid disease. New mechanisms for the critical regulation of TLR-induced cytokine responses are still emerging. Here we find TLR4 complexes localized in LPS-induced dorsal ruffles on the surface of macrophages. We discover that the small GTPase Rab8a is enriched in these ruffles and recruits phosphatidylinositol 3-kinase (PI3K 3) as an effector by interacting directly through its Ras-binding domain. Rab8a and PI3K 3 function to regulate Akt sig..