PXD036641-3
PXD036641 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | Lactate regulates cell cycle and proliferation by remodeling the anaphase promoting complex |
Description | 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. |
HostingRepository | PRIDE |
AnnounceDate | 2023-11-14 |
AnnouncementXML | Submission_2023-11-14_08:45:34.000.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Haopeng Xiao |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Orbitrap Eclipse; Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2022-09-12 05:33:12 | ID requested | |
1 | 2023-02-07 14:22:49 | announced | |
2 | 2023-05-08 15:47:08 | announced | 2023-05-08: Updated project metadata. |
⏵ 3 | 2023-11-14 08:45:42 | announced | 2023-11-14: Updated project metadata. |
Publication List
Liu W, Wang Y, Bozi LHM, Fischer PD, Jedrychowski MP, Xiao H, Wu T, Darabedian N, He X, Mills EL, Burger N, Shin S, Reddy A, Sprenger HG, Tran N, Winther S, Hinshaw SM, Shen J, Seo HS, Song K, Xu AZ, Sebastian L, Zhao JJ, Dhe-Paganon S, Che J, Gygi SP, Arthanari H, Chouchani ET, Lactate regulates cell cycle by remodelling the anaphase promoting complex. Nature, 616(7958):790-797(2023) [pubmed] |
Keyword List
submitter keyword: TPP, lactate, cell cycle |
Contact List
Edward Chouchani | |
---|---|
contact affiliation | Department of Cancer Biology, Dana-Farber Cancer Institute Department of Cell Biology, Harvard Medical School |
contact email | EdwardT_Chouchani@DFCI.HARVARD.EDU |
lab head | |
Haopeng Xiao | |
contact affiliation | Dana-Farber Cancer Institute/Harvard Medical School |
contact email | haopeng_xiao@dfci.harvard.edu |
dataset submitter |
Full Dataset Link List
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PRIDE project URI |
Repository Record List
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