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Multi-omics analysis identifies drivers of protein phosphorylation

ABSTRACT: Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. Phosphorylated peptides (phosphopeptides) can be detected and quantified by mass spectrometry. The abundance of a phosphopeptide is determined by both the abundance of its parent protein and the proportion of target sites that are phosphorylated. We quantified phosphopeptides, proteins, and transcripts in heart, liver, and kidney tissue samples from female and male pair from 58 strains of the Collaborative Cross strain panel. We mapped ~700 phosphorylation quantitative trait loci (phQTL) across the three tissues and applied genetic mediation analysis to identify causal drivers of phosphorylation. We identified kinases, phosphatases, cytokines, and other factors, including both known and potentially novel interactions between target proteins and genes that regulate site-specific phosphorylation. We observed coordination of phosphorylation across multiple sites within a protein and across proteins that form complexes. Our analysis highlights multiple targets of pyruvate dehydrogenase kinase 1 (PDK1), a regulator of mitochondrial function that shows reduced activity in the NZO/HILtJ mouse, a polygenic model of obesity and type 2 diabetes.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Liver, Kidney

SUBMITTER: Tian Zhang

LAB HEAD: Steven Gygi

PROVIDER: PXD032843 | Pride | 2023-02-02

REPOSITORIES: Pride

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			Action	DRS
	Heart_TMT1_Phos_2cv.mzIdentML	Mzid
	Heart_TMT1_Phos_2cv.raw	Raw
	Heart_TMT1_Phos_3cv.mzIdentML	Mzid
	Heart_TMT1_Phos_3cv.raw	Raw
	Heart_TMT2_Phos_2cv.mzIdentML	Mzid

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Project description:Nonalcoholic fatty liver disease (NAFLD) is becoming a primary cause of liver damage in Western society. Nonalcoholic steatohepatitis (NASH) is an advanced stage of NAFLD and may lead to liver cancer. Our previous long-term murine studies have shown the beneficial role of Aquamin, a red marine algae-derived (calcium, magnesium, additional trace elements-rich) supplement, in reducing liver injury and decreasing liver tumor incidence. The main objective of the study was to determine how manifestations and effects of NASH can be mitigated using Aquamin. We hypothesized that mice on a high-fat Western diet (HFWD) with minerals would exhibit less liver injury than mice on a HFWD without minerals. Methods: Two cohorts of MS-NASH mice (8-week-old) were placed on a HFWD with and without minerals for 16 weeks. An additional cohort of MS-NASH mice on the same HFWD was treated with obeticholic acid (OCA). C57BL/6 mice on a regular chow were included as a control. During the in-life phase of the study, weight changes were assessed weekly. At termination, livers were histologically assessed for steatosis and fibrosis by using hematoxylin and eosin, and picrosirius red staining. Liver tissue samples were also subjected to tandem mass tag (TMT) mass-spectroscopic proteomics for protein expression profile in individual mice. Results: Mice on HFWD gained more weight than mice on control diet, but there was no overall change in weight for mice on HFWD, irrespective of interventions. On histological assessment, there was no difference in steatosis between the two high-fat groups, but mice on Aquamin showed reduced picrosirius red staining or collagen deposition as compared to placebo on HFWD mice. Regarding proteomic profile, there was a clear distinction among control and HFWD groups. Placebo (on HFWD) mice were used for comparison. Aquamin intervention altered 91 proteins while OCA altered 84 proteins in liver samples with a 2-fold change. Of these, 57 proteins were common between Aquamin and OCA. Most of the proteins were upregulated. Aquamin upregulated 39 unique pathways (with a p-value <0.05) as assessed by the Reactome database. Some of the pathways significantly impacted by Aquamin were formation of cornified envelope; keratinization; gap junction assembly; type I hemidesmosome assembly; apoptosis-related; plasma lipoprotein assembly, remodeling and clearance; and hedgehog “off” state pathways. Proteins downregulated by OCA are mainly involved in the synthesis of bile acids and bile salts. Conclusion: The addition of dietary minerals may play a protective role in interfering with downstream advancement from steatosis to NASH. Our studies provide mechanistic insight into how mineral supplementation may contribute to the reduction in liver injury and tumor formation (one of the most devastating consequences) of fatty liver disease in the context of HFWD-induced steatosis.

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Multi-omics analysis identifies drivers of protein phosphorylation

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