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Sci. Signal., 11 December 2012
Vol. 5, Issue 254, p. ra90
[DOI: 10.1126/scisignal.2003200]

RESEARCH ARTICLES

TIM Family Proteins Promote the Lysosomal Degradation of the Nuclear Receptor NUR77

Savithri Balasubramanian1*, Satya Keerthi Kota2, Vijay K. Kuchroo3, Benjamin D. Humphreys4, and Terry B. Strom1*

1 Harvard Medical School, Department of Medicine, The Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
2 Institute of Molecular Genetics, CNRS, UMR5535, 1919 Route de Mende, 34293 Montpelier Cedex 5, France.
3 Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, MA 02115, USA.
4 Division of Nephrology, Brigham and Women’s Hospital, Boston, MA 02115, USA.

Abstract: T cell immunoglobulin and mucin domain (TIM) proteins are cell-surface signaling receptors in T cells and scavenger receptors in antigen-presenting cells and kidney tubular epithelia. Here, we demonstrated a function for TIM proteins in mediating the degradation of NUR77, a nuclear receptor implicated in apoptosis and cell survival. TIM proteins interacted with and mediated the lysosomal degradation of NUR77 in a phosphoinositide 3-kinase–dependent pathway. We also showed dynamic cycling of TIM-1 to and from the cell surface through clathrin-dependent constitutive endocytosis. Blocking this process or mutating the phosphatidylserine-binding pocket in TIM-1 abrogated TIM-1–mediated degradation of NUR77. In an in vitro model of kidney injury, silencing TIM-1 increased NUR77 abundance and decreased epithelial cell survival. These results show that TIM proteins may affect immune cell function and the response of the kidney to injury.

* To whom correspondence should be addressed. E-mail: skota{at}bidmc.harvard.edu (S.B.); tstrom{at}bidmc.harvard.edu (T.B.S.)

Citation: S. Balasubramanian, S. K. Kota, V. K. Kuchroo, B. D. Humphreys, T. B. Strom, TIM Family Proteins Promote the Lysosomal Degradation of the Nuclear Receptor NUR77. Sci. Signal. 5, ra90 (2012).

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