Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs

Lymphocyte activation gene 3 (LAG3) has emerged as a promising cancer immunotherapy target, but the mechanism underlying LAG3 activation upon ligand engagement remains elusive. Here, LAG3 was found to undergo robust non-K48-linked polyubiquitination upon ligand engagement, which promotes LAG3's inhibitory function instead of causing degradation. This ubiquitination could be triggered by the engagement of major histocompatibility complex class II (MHC class II) and membrane-bound (but not soluble) fibrinogen-like protein 1 (FGL1). LAG3 ubiquitination, mediated redundantly by the E3 ligases c-Cbl and Cbl-b, disrupted the membrane binding of the juxtamembrane basic residue-rich sequence, thereby stabilizing the…

• NN
  National Natural Science Foundation of China

  Awards: 32471268, 82350110
• CA
  Chinese Academy of Sciences

  Awards: XDB0990000, YSBR-014
• MO
  Ministry of Science and Technology of the People's Republic of China

  Award: 2023YFA1800200
• SA
  Science and Technology Commission of Shanghai Municipality

  Award: 23J21901300
• SU
  ShanghaiTech University
• NI
  National Institutes of Health

  Awards: P01 AI108545, R01 AI144422
• NK
  National Key Research and Development Program of China

  Award: 2019YFA0111000
• PO
  Program of Shanghai Academic Research Leader