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Sci Signal. 2012 Dec 11;5(254):ra90. doi: 10.1126/scisignal.2003200.

TIM family proteins promote the lysosomal degradation of the nuclear receptor NUR77.

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1
Harvard Medical School, Department of Medicine, The Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. skota@bidmc.harvard.edu

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.

PMID:
23233528
PMCID:
PMC3767312
DOI:
10.1126/scisignal.2003200
[Indexed for MEDLINE]
Free PMC Article
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