Cytomegalovirus gp40/m152 uses TMED10 as ER anchor to retain MHC class I

  • In a virus infection, major histocompatibility complex (MHC) class I molecules present viral antigens from infected cells to CD8+ cytotoxic T cells in a process called antigen presentation. Recognition of the viral epitope in the context of the class I molecule activates T cells to kill infected cells and thus eradicate viral infection. Viruses have evolved to perturb antigen presentation on MHC class I, and thus thwart the host immune response against the infection. For example, they encode proteins, called immunoevasins, that adversely affect one or several steps of the antigen presentation pathway. One such immunoevasin is m152/gp40 from the murine cytomegalovirus. In the presence of gp40, MHC class I molecules fail to leave the early secretory pathway(the endoplasmic reticulum (ER), the ER-Golgi intermediate compartment (ERGIC), and the cis-Golgi), and this prevents T cell recognition. Our work here shows for the first time that gp40 and class I molecules interact. The complex of gp40/class I circulates in the early secretory pathway. For this ER/ERGIC/cis-Golgi localization of the complex, the linker connecting the lumenal to the transmembrane domain of gp40 turned out to be necessary. This linker most likely binds to TMED10, a member of the p24 family of ER/Golgi transmembrane proteins, which anchors gp40 in the early secretory pathway. Deletion of TMED10 restores cell surface class I levels in the presence of gp40, most likely by destabilizing gp40 in a yet unknown fashion. We also show that the trafficking signals in the cytosolic tail of TMED10 (FF and KKxxx) are required for the ER localization of gp40. We have thus discovered the first viral client protein of the p24 family, and we have shown the first evidence that the p24 proteins can be exploited for viral evasion strategies.

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Meta data
Publishing Institution:IRC-Library, Information Resource Center der Jacobs University Bremen
Granting Institution:Jacobs Univ.
Author:Venkat Raman Ramnarayan
Referee:Klaudia Brix, Marcus Gröttrup
Advisor:Sebastian Springer
Persistent Identifier (URN):urn:nbn:de:gbv:579-opus-1008257
Document Type:PhD Thesis
Date of Successful Oral Defense:2018/11/06
Date of First Publication:2018/10/18
Academic Department:Life Sciences & Chemistry
PhD Degree:Biochemistry
Focus Area:Health
Call No:2018/21

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