CYRI/FAM49B negatively regulates RAC1-driven cytoskeletal remodelling and protects against bacterial infection

• Published in: Nature microbiology Vol. 4; no. 9; pp. 1516 - 1531
• Main Authors: Yuki, Kyoko E., Marei, Hadir, Fiskin, Evgenij, Eva, Megan M., Gopal, Angelica A., Schwartzentruber, Jeremy A., Majewski, Jacek, Cellier, Mathieu, Mandl, Judith N., Vidal, Silvia M., Malo, Danielle, Dikic, Ivan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2019; Nature Publishing Group
• Subjects: 14/63; 59/5; 631/326/41/2531; 631/326/41/2533; 631/326/421; 631/326/88; 631/80/128; 64/60; 82/29; 82/58; 82/80; 96/106; 96/109; 96/21; 96/31; 96/35; 96/95; Actin; Actins - metabolism; Animals; Bacteria; Bacterial infections; Bacterial Infections - metabolism; Bacterial Infections - microbiology; Bacterial Infections - prevention & control; Bacterial Load; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biomedical and Life Sciences; Cell adhesion & migration; Cell migration; Cytoskeleton; Cytoskeleton - genetics; Cytoskeleton - metabolism; Disease Resistance - genetics; Genomes; Guanosine triphosphatases; HEK293 Cells; HeLa Cells; Host-Pathogen Interactions; Humans; Infections; Infectious Diseases; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Listeria monocytogenes; Listeria monocytogenes - metabolism; Listeria monocytogenes - physiology; Macrophages - microbiology; Macrophages - pathology; Medical Microbiology; Mice; Microbiology; Microbiology and Parasitology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mutagenesis; Mutation; Mycobacterium tuberculosis - metabolism; Mycobacterium tuberculosis - physiology; Parasitology; Pathogenicity; Pathogens; Phagocytes; Phagocytosis; Polymerization; Protein Binding; Proteins; Public health; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Salmonella; Salmonella typhimurium - metabolism; Salmonella typhimurium - physiology; Signal Transduction; Survival Analysis; Tuberculosis; Virology
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-019-0484-8

Salmonella presents a global public health concern. Central to Salmonella pathogenicity is an ability to subvert host defences through strategically targeting host proteins implicated in restricting infection. Therefore, to gain insight into the host–pathogen interactions governing Salmonella infection, we performed an in vivo genome-wide mutagenesis screen to uncover key host defence proteins. This revealed an uncharacterized role of CYRI (FAM49B) in conferring host resistance to Salmonella infection. We show that CYRI binds to the small GTPase RAC1 through a conserved domain present in CYFIP proteins, which are known RAC1 effectors that stimulate actin polymerization. However, unlike CYFIP proteins, CYRI negatively regulates RAC1 signalling, thereby attenuating processes such as macropinocytosis, phagocytosis and cell migration. This enables CYRI to counteract Salmonella at various stages of infection, including bacterial entry into non-phagocytic and phagocytic cells as well as phagocyte-mediated bacterial dissemination. Intriguingly, to dampen its effects, the bacterial effector SopE, a RAC1 activator, selectively targets CYRI following infection. Together, this outlines an intricate host–pathogen signalling interplay that is crucial for determining bacterial fate. Notably, our study also outlines a role for CYRI in restricting infection mediated by Mycobacterium tuberculosis and Listeria monocytogenes . This provides evidence implicating CYRI cellular functions in host defence beyond Salmonella infection. A mouse mutagenesis screen identifies CYRI (FAM49B) as a host protection factor against Salmonella infection. CYRI negatively regulates RAC1 signalling to interfere with bacterial entry and dissemination.