Lactate regulates cell cycle by remodelling the anaphase promoting complex

Weihai Liu, Yun Wang, Luiz H. M. Bozi, Patrick D. Fischer, Mark P. Jedrychowski, Haopeng Xiao, Tao Wu, Narek Darabedian, Xiadi He, Evanna L. Mills, Nils Burger, Sanghee Shin, Anita Reddy, Hans-Georg Sprenger, Nhien Tran, Sally Winther, Stephen M. Hinshaw, Jingnan Shen, Hyuk-Soo Seo, Kijun Song, Andrew Z. Xu, Luke Sebastian, Jean J. Zhao, Sirano Dhe-Paganon, Jianwei Che, Steven P. Gygi, Haribabu Arthanari and Edward T. Chouchani ()
Additional contact information
Weihai Liu: Dana–Farber Cancer Institute
Yun Wang: Dana–Farber Cancer Institute
Luiz H. M. Bozi: Dana–Farber Cancer Institute
Patrick D. Fischer: Dana–Farber Cancer Institute
Mark P. Jedrychowski: Dana–Farber Cancer Institute
Haopeng Xiao: Dana–Farber Cancer Institute
Tao Wu: Harvard Medical School
Narek Darabedian: Dana–Farber Cancer Institute
Xiadi He: Dana–Farber Cancer Institute
Evanna L. Mills: Dana–Farber Cancer Institute
Nils Burger: Dana–Farber Cancer Institute
Sanghee Shin: Dana–Farber Cancer Institute
Anita Reddy: Dana–Farber Cancer Institute
Hans-Georg Sprenger: Dana–Farber Cancer Institute
Nhien Tran: Dana–Farber Cancer Institute
Sally Winther: Dana–Farber Cancer Institute
Stephen M. Hinshaw: Stanford University
Jingnan Shen: Sun Yat-sen University
Hyuk-Soo Seo: Dana–Farber Cancer Institute
Kijun Song: Dana–Farber Cancer Institute
Andrew Z. Xu: Dana–Farber Cancer Institute
Luke Sebastian: Dana–Farber Cancer Institute
Jean J. Zhao: Dana–Farber Cancer Institute
Sirano Dhe-Paganon: Dana–Farber Cancer Institute
Jianwei Che: Dana–Farber Cancer Institute
Steven P. Gygi: Harvard Medical School
Haribabu Arthanari: Dana–Farber Cancer Institute
Edward T. Chouchani: Dana–Farber Cancer Institute

Nature, 2023, vol. 616, issue 7958, 790-797

Abstract: Abstract Lactate is abundant in rapidly dividing cells owing to the requirement for elevated glucose catabolism to support proliferation1–6. However, it is not known whether accumulated lactate affects the proliferative state. Here we use a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we identify a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodelling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We find that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. This mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient-replete growth phase to stimulate timed opening of APC/C, cell division and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodelling and can overcome anti-mitotic pharmacology via mitotic slippage. In sum, we define a biochemical mechanism through which lactate directly regulates protein function to control the cell cycle and proliferation.

Date: 2023
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-023-05939-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:616:y:2023:i:7958:d:10.1038_s41586-023-05939-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-05939-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().