PXD021531

PXD021531 is an original dataset announced via ProteomeXchange.

Title	CHIP phosphorylation regulates proteostasis
Description	Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) is an important regulator of proteostasis in many cells, having E3-ligase and chaperone functions and often directing damaged proteins towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we demonstrate that CHIP-mediated protein turnover is markedly post-translationally enhanced by direct protein kinase G (PKG) phosphorylation at S20 (mouse, S19 human). This increases CHIP binding affinity to Hsc70, CHIP protein halflife, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. PKGmediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. PKG activation provides post-translational enhancement of protein quality control via CHIP.
HostingRepository	PRIDE
AnnounceDate	2021-09-09
AnnouncementXML	Submission_2021-09-09_08:58:21.513.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Vidya Venkatraman
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2020-09-17 00:52:17	ID requested
⏵ 1	2021-09-09 08:58:22	announced

Ranek MJ, Oeing C, Sanchez-Hodge R, Kokkonen-Simon KM, Dillard D, Aslam MI, Rainer PP, Mishra S, Dunkerly-Eyring B, Holewinski RJ, Virus C, Zhang H, Mannion MM, Agrawal V, Hahn V, Lee DI, Sasaki M, Van Eyk JE, Willis MS, Page RC, Schisler JC, Kass DA, CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury. Nat Commun, 11(1):5237(2020) [pubmed]

submitter keyword: Rat Myocyctes phosphorylation CHIP PKG cardiac ischemia

Dr. Jennifer Van Eyk
contact affiliation	Cedars-Sinai Medical Center
contact email	jennifer.vaneyk@cshs.org
lab head
Vidya Venkatraman
contact affiliation	Cedars-Sinai Medical Center
contact email	vidya.venkatraman@cshs.org
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/2021/09/PXD021531

PRIDE project URI

• PRIDE
  1. PXD021531
     1. Label: PRIDE project
     2. Name: CHIP phosphorylation regulates proteostasis