title: Autophagy-independent functions of UVRAG are essential for peripheral naive T-cell homeostasis.
abstract: 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 of Uvrag in 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.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Samia
authors.initials: S
authors.lastname: Afzal
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Department of Urology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka. 812-8582, Japan;
authors.forename: Momoe
authors.initials: M
authors.lastname: Itsumi
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Yasser
authors.initials: Y
authors.lastname: Abouelkheer
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Department of Infection and Immunity, Luxembourg Institute of Health, 84, Val Fleuri, L-1526, Luxembourg; and.
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Claire
authors.initials: C
authors.lastname: Hong
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Wanda Y
authors.initials: WY
authors.lastname: Li
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sylvester
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Syed O
authors.initials: SO
authors.lastname: Gilani
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Pathogens and Immunity Department, Australian National University, Acton Act 2601, Canberra, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Jillian
authors.initials: J
authors.lastname: Haight
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Annick J
authors.initials: AJ
authors.lastname: You-Ten
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Lin
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; tmak@uhnres.utoronto.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D017353:Gene Deletion; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D025521:Tumor Suppressor Proteins / Q000276:immunology* / Q000302:isolation & purification
chemical_list: D025521:Tumor Suppressor Proteins; C512859:UVRAG protein, mouse
keywords: T-cell homeostasis; UVRAG-deficient mice; autophagy; embryonic lethality