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

  • Experimental and¬†Molecular Immunology
January 27, 2015 By:
  • Afzal S
  • Hao Z
  • Itsumi M
  • Abouelkheer Y
  • Brenner D
  • Gao Y
  • Wakeham A
  • Hong C
  • Li WY
  • Sylvester J
  • Gilani SO
  • Brustle A
  • Haight J
  • You-Ten AJ
  • Lin GH
  • Inoue S
  • Mak TW.

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 naive peripheral T-cell homeostasis.

2015 Jan. Proc Natl Acad Sci U S A.112(4):1119-24. Epub 2015 Jan 12.
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