Lactate regulates cell cycle by remodelling the anaphase promoting complex

• Published in: Nature (London) Vol. 616; no. 7958; pp. 790 - 797
• Main Authors: Liu, Weihai, Wang, Yun, Bozi, Luiz H. M., Fischer, Patrick D., Jedrychowski, Mark P., Xiao, Haopeng, Wu, Tao, Darabedian, Narek, He, Xiadi, Mills, Evanna L., Burger, Nils, Shin, Sanghee, Reddy, Anita, Sprenger, Hans-Georg, Tran, Nhien, Winther, Sally, Hinshaw, Stephen M., Shen, Jingnan, Seo, Hyuk-Soo, Song, Kijun, Xu, Andrew Z., Sebastian, Luke, Zhao, Jean J., Dhe-Paganon, Sirano, Che, Jianwei, Gygi, Steven P., Arthanari, Haribabu, Chouchani, Edward T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.04.2023; Nature Publishing Group
• Subjects: 631/80/304; 631/80/86; 82; 82/58; Accumulation; Anaphase; Anaphase-promoting complex; Anaphase-Promoting Complex-Cyclosome - metabolism; Catabolism; Cell Cycle; Cell Cycle Proteins - metabolism; Cell division; Humanities and Social Sciences; Humans; Lactic acid; Lactic Acid - metabolism; Mass spectrometry; Metabolism; Mitosis; multidisciplinary; Pharmacology; Proteins; Proteomes; Science; Science (multidisciplinary); Scientific imaging; SUMO protein
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-05939-3

Lactate is abundant in rapidly dividing cells owing to the requirement for elevated glucose catabolism to support proliferation 1 – 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. Discovery of a biochemical mechanism through which lactate binds and inhibits the SUMO protease SENP1, stimulating timed degradation of cell cycle proteins, and resulting in mitotic exit.