PXD036641

PXD036641 is an original dataset announced via ProteomeXchange.

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

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.

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]

submitter keyword: TPP, lactate, cell cycle

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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/02/PXD036641

PRIDE project URI

• PRIDE
  1. PXD036641
     1. Label: PRIDE project
     2. Name: Lactate regulates cell cycle and proliferation by remodeling the anaphase promoting complex