Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation

Rut Valdor, Enric Mocholi, Yair M. Botbol, Ignacio Guerrero-Ros, Dinesh Chandra, Hiroshi Koga, Claudia Gravekamp, Ana Maria Cuervo, Fernando Macian-Juan

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Chaperone-mediated autophagy (CMA) targets soluble proteins for lysosomal degradation. Here we found that CMA was activated in T cells in response to engagement of the T cell antigen receptor (TCR), which induced expression of the CMA-related lysosomal receptor LAMP-2A. In activated T cells, CMA targeted the ubiquitin ligase Itch and the calcineurin inhibitor RCAN1 for degradation to maintain activation-induced responses. Consequently, deletion of the gene encoding LAMP-2A in T cells caused deficient in vivo responses to immunization or infection with Listeria monocytogenes. Impaired CMA activity also occurred in T cells with age, which negatively affected their function. Restoration of LAMP-2A in T cells from old mice resulted in enhancement of activation-induced responses. Our findings define a role for CMA in regulating T cell activation through the targeted degradation of negative regulators of T cell activation.

Original languageEnglish (US)
Pages (from-to)1046-1054
Number of pages9
JournalNature Immunology
Volume15
Issue number11
DOIs
StatePublished - Oct 25 2014

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Autophagy
T-Lymphocytes
Gene Deletion
Listeria monocytogenes
Ligases
Ubiquitin
T-Cell Antigen Receptor
Proteolysis
Immunization
Infection

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation. / Valdor, Rut; Mocholi, Enric; Botbol, Yair M.; Guerrero-Ros, Ignacio; Chandra, Dinesh; Koga, Hiroshi; Gravekamp, Claudia; Cuervo, Ana Maria; Macian-Juan, Fernando.

In: Nature Immunology, Vol. 15, No. 11, 25.10.2014, p. 1046-1054.

Research output: Contribution to journalArticle

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