Autophagy Induction by the pathogen Receptor CD46

P. E. Joubert, G. Meiffren, I. P. Gregoire, G. Pontini, C. Richetta, M. Flacher, O. Azocar, P. O. Vidalain, M. Vidal, V. Lotteau, P. Codogno, C. Rabourdin-Combe and M. Faure

(2009) Cell Host Microbe 6(4):354-366.

Speaker: Hsuan-Yun Hu (胡瑄耘)                                        Time: 14:00~15:00, Mar. 3, 2010

Commentator: Dr. Yee-Shin Lin (林以行老師)                    Place: Room 601

Abstract:

        CD46 (membrane cofactor protein; MCP) is a member of regulatory complement activation family. Two different cytoplasmic tails are found in CD46 isoforms, Cyt-1 and Cyt-2, which are coexpressed in human somatic cells. CD46 binds several pathogens such as measles virus, adenovirus B and D, human herpesvirus 6 and Streptococcus pyogenes (group A Streptococcus, GAS).(1) Autophagy is a cellular homeostatic process that is responsible for clearance of long-lived proteins, damaged organelles and aggregated proteins in cytoplasm. It plays a role in innate and adaptive immunity against pathogens. GAS could be eliminated by autophagic machinery.(2) Pattern recognition receptors such as Toll-like receptors trigger autophagy as a defense mechanism against invasive of pathogens.(3) However, the detailed mechanisms about the receptors-induced autophagy are still unclear. In this paper, the authors clarified the ubiquitous surface receptor, CD46-induced autophagy that affects pathogen invasion. They showed that antibody-driven CD46 crosslinking induced autophagosome formation without inhibiting it maturation. Using yeast two-hybrid screen, they found one Cyt-1-interaction protein, Golgi-associated PDZ and coiled-coil motif-containing protein (GOPC). GOPC is a scaffold protein that contains two coiled-coil domains (CC) and a PDZ domain. It interacted with CD46-Cyt-1 via the PDZ domain and bound BECN1 via the CC domain and associated with the autophagosome formation complex VPS34/BECN1. CD46 induces autophagy through GOPC binding with BECN1 that associates with VPS34. Two pathogens, measles virus and GAS bound by CD46 induce autophagy through the CD46-Cyt-1/GOPC pathway, which degrades GAS. In summary, a cell surface pathogen receptor CD46 reserves as a switch of autophagy and is critical for controlling early infection of pathogens.

References:

1.          Riley-Vargas, R. C., D. B. Gill, C. Kemper, M. K. Liszewski, and J. P. Atkinson. 2004. CD46: expanding beyond complement regulation. Trends Immunol 25:496-503.

2.          Nakagawa, I., A. Amano, N. Mizushima, A. Yamamoto, H. Yamaguchi, T. Kamimoto, A. Nara, J. Funao, M. Nakata, K. Tsuda, S. Hamada, and T. Yoshimori. 2004. Autophagy defends cells against invading group A Streptococcus. Science 06:1037-40.

3.          Delgado, M. A., R. A. Elmaoued, A. S. Davis, G. Kyei, and V. Deretic. 2008. Toll-like receptors control autophagy. EMBO J 27:1110-21.