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

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

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70 Scopus citations


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
Issue number11
StatePublished - Oct 25 2014


ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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