4.7 Article

K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation

期刊

NATURE IMMUNOLOGY
卷 16, 期 12, 页码 1253-1262

出版社

NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3258

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资金

  1. National Key Basic Research Program of China [2010CB911903, 2013CB530500]
  2. National Natural Science Foundation of China [81222039, 81172851, 81471566, 31170863, 81123006, 31390431]
  3. National Excellent Doctoral Dissertation of China [200775]
  4. Shanghai Committee of Science and Technology [11QH1402900]

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The key molecular mechanisms that control signaling via T cell antigen receptors (TCRs) remain to be fully elucidated. Here we found that Nrdp1, a ring finger-type E3 ligase, mediated Lys33 (K33)-linked polyubiquitination of the signaling kinase Zap70 and promoted the dephosphorylation of Zap70 by the acidic phosphatase-like proteins Sts1 and Sts2 and thereby terminated early TCR signaling in CD8(+) T cells. Nrdp1 deficiency significantly promoted the activation of naive CD8(+) T cells but not that of naive CD4(+) T cells after engagement of the TCR. Nrdp1 interacted with Zap70 and with Sts1 and Sts2 and connected K33 linkage of Zap70 to Sts1- and Sts2-mediated dephosphorylation. Our study suggests that Nrdp1 terminates early TCR signaling by inactivating Zap70 and provides new mechanistic insights into the non-proteolytic regulation of TCR signaling by E3 ligases.

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