CDK1, the Other 'Master Regulator' of Autophagy. Issue 2 (February 2021)

• Record Type: Journal Article
• Authors: Odle, Richard I.; Florey, Oliver; Ktistakis, Nicholas T.; Cook, Simon J.
• Is Part Of: Trends in cell biology. Volume 31:Issue 2(2021)
• Page Start: 95
• Page End: 107
• Publication Date: 2021-02
• Subjects: autophagy -- CDK1 -- mitosis -- mTORC1 -- translation; Cytology -- Periodicals; Cytology -- Research -- Periodicals; 571.6
• DOI: 10.1016/j.tcb.2020.11.001
• Languages: English
• ISSNs: 0962-8924

Abstract

Abstract : Autophagy and cap-dependent mRNA translation are tightly regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signalling complex in response to nutrient availability. However, the regulation of these processes, and mTORC1 itself, is different during mitosis, and this has remained an area of significant controversy; for example, studies have argued that autophagy is either repressed or highly active during mitosis. Recent studies have shown that autophagy initiation is repressed, and cap-dependent mRNA translation is maintained during mitosis despite mTORC1 activity being repressed. This is achieved in large part by a switch from mTORC1- to cyclin-dependent kinase 1 (CDK1)–mediated regulation. Here, we review the history and recent advances and seek to present a unifying model to inform the future study of autophagy and mTORC1 during mitosis. Highlights: Class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin complex 1 (mTORC1) signalling is inhibited during mitosis, so that autophagy and cap-dependent translation are uncoupled from nutrient availability. During mitosis, cyclin-dependent kinase 1 (CDK1) promotes phosphorylation of RAPTOR, causing dissociation of mTORC1 from lysosomes, thereby inhibiting it. CDK1 substitutes for inhibited mTORC1 by phosphorylating ATG13, ULK1, and ATG14 at canonical mTOR sites and also phosphorylates VPS34. In addition, WIPI2 undergoes ubiquitination and degradation. This ensures a system-wide repression of autophagy during mitosis. CDK1 also takes over the mTORC1-dependent phosphorylation of eukaryotic translation initiation factor 4E-binding proteins (4E-BPs) to maintain cap-dependent translation of 5′ terminal oligopyrimidine (TOP) mRNAs. The ULK1 complex has roles in mitotic division, which may be dependent on its phosphorylation by CDK1. There is ongoing debate as to whether this is linked to ULK1's role in autophagy or by phosphorylating substrates such as Mad1.