Phagocytosis: Mitochondria and Phagosomes: Better Together

RESEARCH HIGHLIGHTS S.Bradbrook/NPG

PHAGOCYTOSIS Mitochondria and phagosomes: better together

Phagocyte destruction of engulfed through TLRs leads to MST1 and Downstream of RAC1–GTP, it was microorganisms depends on the MST2 activation that is required for shown that the E3 ubiquitin ligase production of bactericidal reac- intracellular killing of bacteria. TRAF6 catalyses the Lys63-linked tive oxygen species (ROS) by both In the absence of MST1 and polyubiquitylation and further activa- the phagosomal NADPH oxidase MST2, the induction of mitochon- tion of RAC1. A constitutively active pathway and mitochondria, but drial ROS production after bacterial form of RAC1 was ubiquitylated to a the mechanisms by which ROS infection was markedly impaired, greater extent than wild-type RAC1, production is coordinated spatially despite the normal ability of cDKO whereas RAC1–GDP was resistant to and temporally have been unclear. mitochondria to generate ROS in ubiquitylation. In keeping with this, This study describes a new signalling response to electron-transport inhibi- the impaired activation of RAC1 in pathway downstream of Toll-like tors. The authors showed that cDKO TLR-stimulated cDKO macrophages receptor (TLR) stimulation by which macrophages had defective recruit- correlated with less ubiquitylation of the kinases MST1 and MST2 regulate ment of mitochondria to phagocy- RAC1. As TRAF6 binds selectively to the trafficking of mitochondria to tosed bacteria as a result of disrupted inactive RAC1, the polyubiquityla- phagosomes to deliver ROS. F-actin cytoskeletal organisation tion and further activation of RAC1 Deficiency of MST1 in humans downstream of defective activation by TRAF6 resulted in the release of results in a severe immunodeficiency of the RAC GTPase proteins. Mice TRAF6 to bind the mitochondrial syndrome, and mice with haemato expressing a constitutively active form complex I assembly factor ECSIT. poietic cell-specific knockout of of RAC1 in cDKO myeloid lineages The TRAF6–ECSIT complex in turn Mst1 and Mst2 have multiple, recur- had normal F-actin organisation, mediates mitochondrion−phagosome rent bacterial infections, which is normal mitochondrion−phagosome juxtaposition and ROS production. indicative of an innate immune defect. juxtaposition and normal production As a constitutively active form of innate immune Indeed, mice generated for this study of ROS after TLR stimulation. RAC1 fully rescued the phenotype with double knockout of Mst1 and Next, the authors looked at the of cDKO mice, the authors conclude activation of Mst2 in myeloid cells (referred to as mechanism by which TLR-stimulated that RAC1–GTP — downstream of phagocytes cDKO mice) were more susceptible MST1 and MST2 activate RAC MST1 and MST2 activated by TLR through TLRs to bacterial peritonitis than wild-type proteins to positively regulate signalling — has a crucial role in leads to MST1 controls despite an enhanced inflam- phagosome-mediated bacterial coordinating mitochondrial ROS pro- matory response, and cDKO phago- killing. MST2 co-precipitated with duction with its already established and MST2 cytes were defective in their clearance and phosphorylated protein kinase role in the activation of NADPH activation that of intracellular bacteria. Furthermore, Cα (PKCα), which in turn inter- oxidase. is required for stimulation of cell-surface TLRs acted with and phosphorylated the Kirsty Minton (TLR1, TLR2 and TLR4) was shown RHO–GDP dissociation inhibitor intracellular ORIGINAL RESEARCH PAPER Geng, J. et al. to activate MST1 and MST2 in a LYGDI (also known as ARHGDIB), Kinases Mst1 and Mst2 positively regulate killing of MYD88-dependent manner. Together, thereby disrupting its interaction with phagocytic induction of reactive oxygen species the results indicate that innate RAC–GDP to enable RAC protein and bactericidal activity. Nat. Immunol. http://dx. bacteria doi.org/10.1038/ni.3268 (2015) immune activation of phagocytes activation by GTP binding.

NATURE REVIEWS | IMMUNOLOGY VOLUME 15 | NOVEMBER 2015