Negative regulation of APC/C activation by MAPK-mediated attenuation of Cdc20Slp1 under stress

Elife. 2024 Oct 16:13:RP97896. doi: 10.7554/eLife.97896.

Abstract

Mitotic anaphase onset is a key cellular process tightly regulated by multiple kinases. The involvement of mitogen-activated protein kinases (MAPKs) in this process has been established in Xenopus egg extracts. However, the detailed regulatory cascade remains elusive, and it is also unknown whether the MAPK-dependent mitotic regulation is evolutionarily conserved in the single-cell eukaryotic organisms such as fission yeast (Schizosaccharomyces pombe). Here, we show that two MAPKs in S. pombe indeed act in concert to restrain anaphase-promoting complex/cyclosome (APC/C) activity upon activation of the spindle assembly checkpoint (SAC). One MAPK, Pmk1, binds to and phosphorylates Slp1Cdc20, the co-activator of APC/C. Phosphorylation of Slp1Cdc20 by Pmk1, but not by Cdk1, promotes its subsequent ubiquitylation and degradation. Intriguingly, Pmk1-mediated phosphorylation event is also required to sustain SAC under environmental stress. Thus, our study establishes a new underlying molecular mechanism of negative regulation of APC/C by MAPK upon stress stimuli, and provides a previously unappreciated framework for regulation of anaphase entry in eukaryotic cells.

Keywords: APC/C; MAPK; S. pombe; SAC; Slp1/Cdc20; anaphase-promoting complex/cyclosome; cell biology; phosphorylation; spindle assembly checkpoint; ubiquitylation.

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome* / metabolism
  • Cdc20 Proteins* / genetics
  • Cdc20 Proteins* / metabolism
  • Mitogen-Activated Protein Kinases* / genetics
  • Mitogen-Activated Protein Kinases* / metabolism
  • Phosphorylation
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism
  • Schizosaccharomyces* / metabolism
  • Stress, Physiological

Substances

  • Anaphase-Promoting Complex-Cyclosome
  • Cdc20 Proteins
  • Mitogen-Activated Protein Kinases
  • Schizosaccharomyces pombe Proteins