Autophagy-independent functions of UVRAG are essential for peripheral naive T-cell homeostasis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 4; pp. 1119 - 1124
• Main Authors: Afzal, Samia, Hao, Zhenyue, Itsumi, Momoe, Abouelkheer, Yasser, Brenner, Dirk, Gao, Yunfei, Wakeham, Andrew, Hong, Claire, Li, Wanda Y., Sylvester, Jennifer, Gilani, Syed O., Brüstle, Anne, Haight, Jillian, You-Ten, Annick J., Lin, Gloria H. Y., Inoue, Satoshi, Mak, Tak W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27-01-2015; National Acad Sciences
• Subjects: Animals; Autophagy - genetics; Autophagy - immunology; Biological Sciences; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cellular biology; Gene Deletion; Gene expression; Homeostasis; Homeostasis - genetics; Homeostasis - immunology; Immunity, Cellular; Lymphocytes; Lymphocytic Choriomeningitis - genetics; Lymphocytic Choriomeningitis - immunology; Lymphocytic choriomeningitis virus - immunology; Mice; Mice, Knockout; Tumor Suppressor Proteins - immunology; Tumor Suppressor Proteins - isolation & purification; Tumors; Ultraviolet radiation; UVRAG-deficient mice; autophagy; T-cell homeostasis; embryonic lethality
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1423588112

UV radiation resistance-associated gene (UVRAG) encodes a tumor suppressor with putative roles in autophagy, endocytic trafficking, and DNA damage repair but its in vivo role in T cells is unknown. Because conditional homozygous deletion ofUvragin mice results in early embryonic lethality, we generated T-cell–specific UVRAG-deficient mice that lacked UVRAG expression specifically in T cells. This loss of UVRAG led to defects in peripheral homeostasis that could not be explained by the increased sensitivity to cell death and impaired proliferation observed for other autophagy-related gene knockout mice. Instead, UVRAG-deficient T-cells exhibited normal mitochondrial clearance and activation-induced autophagy, suggesting that UVRAG has an autophagy-independent role that is critical for peripheral naive T-cell homeostatic proliferation. In vivo, T-cell–specific loss of UVRAG dampened CD8⁺T-cell responses to LCMV infection in mice, delayed viral clearance, and impaired memory T-cell generation. Our data provide novel insights into the control of autophagy in T cells and identify UVRAG as a new regulator of naïve peripheral T-cell homeostasis.