Proteomics

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Lactate regulates cell cycle and proliferation by remodeling the anaphase promoting complex


ABSTRACT: Lactate is abundant in rapidly dividing cells, due to the requirement for elevated glucose catabolism to support proliferation. However, it is not known whether accumulated lactate affects the proliferative state. Here, we deploy a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From this data, we elucidate a mechanism of cell cycle regulation whereby accumulated lactate activates the anaphase promoting complex (APC/C). Remodeling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We discover 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 are required to reorient APC/C to allow UBE2C binding and thus increase APC/C activity. This direct regulation of APC/C by lactate is required to stimulate timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative mammalian cells. The above 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, we show that aberrant remodeling of APC/C by lactate occurs when lactate concentrations are chronically elevated, which is a hallmark of numerous cancers. Moreover, persistent lactate accumulation overcomes anti-mitotic pharmacology to drive mitotic slippage via the newfound mode of APC/C activation. Taken together, we define a biochemical mechanism through which lactate directly regulates protein function to control cell cycle and proliferation.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Haopeng Xiao  

LAB HEAD: Edward Chouchani

PROVIDER: PXD036641 | Pride | 2023-02-07

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
1_TPP_data_table.xlsx Xlsx
2_synchronized__cells_proteomics.xlsx Xlsx
3_sumoylation_IP.xlsx Xlsx
JM04804.raw Raw
JM04805.raw Raw
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Publications


Lactate is abundant in rapidly dividing cells owing to the requirement for elevated glucose catabolism to support proliferation<sup>1-6</sup>. 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 o  ...[more]

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