Dataset Information

Proteomic investigations of human HERC2 mutants: insights into the pathobiology of a neurodevelopmental disorder

ABSTRACT: HERC2 is a giant protein with E3 ubiquitin ligase activity and other known and suspected functions. Mutations of HERC2 are implicated in the pathogenesis of various cancers and result in various severe neurological conditions in Herc2-mutant mice. Recently, a pleotropic autosomal recessive HERC2-associated syndrome of intellectual disability, autism and variable neurological deficits was described; its pathogenetic basis is largely unknown. Using peripheral blood-derived lymphoblasts from 3 persons with homozygous HERC2 variants and 14 age- and gender-matched controls, we performed unbiased HPLC-tandem mass spectrometry-based proteomic analyses to provide insights into HERC2-mediated pathobiology. We found that out of 3427 detected proteins, there were 812 differentially expressed proteins between HERC2-cases vs. controls. 184 canonical pathways were enriched after FDR adjustment, including mitochondrial function, energy metabolism, EIF2 signaling, immune functions, ubiquitination and DNA repair. Ingenuity Pathway Analysis® identified 209 upstream regulators that could drive the differential expression, prominent amongst which were neurodegeneration-associated proteins. Differentially expressed protein interaction networks highlighted themes of immune function/dysfunction, regulation of cell cycle/cell death, and energy metabolism. Overall, the analysis of the HERC2-associated proteome revealed striking differential protein expression between cases and controls. The large number of differentially expressed proteins likely reflects HERC2’s multiple domains and numerous interacting proteins. Our canonical pathway and protein interaction network findings suggest derangements of multiple pathways in HERC2-associated disease.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Blood

DISEASE(S): Autism Spectrum Disorder

SUBMITTER: Kathleen Lundberg

LAB HEAD: Marvin Natowicz

PROVIDER: PXD012644 | Pride | 2019-03-27

REPOSITORIES: Pride

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Publications

Proteomic investigations of human HERC2 mutants: Insights into the pathobiology of a neurodevelopmental disorder.

Abraham Joseph R JR Barnard John J Wang Heng H Noritz Garey H GH Yeganeh Mehdi M Buhas Daniela D Natowicz Marvin R MR

Biochemical and biophysical research communications 20190319 2

HERC2 is a giant protein with E3 ubiquitin ligase activity and other known and suspected functions. Mutations of HERC2 are implicated in the pathogenesis of various cancers and result in severe neurological conditions in Herc2-mutant mice. Recently, a pleotropic autosomal recessive HERC2-associated syndrome of intellectual disability, autism and variable neurological deficits was described; its pathogenetic basis is largely unknown. Using peripheral blood-derived lymphoblasts from 3 persons with ...[more]

PMID: 30902390

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Project description:Herein we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n=3) were compared with littermate controls (n=3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average P = 0.0082; cystatin A, human orthologue); slc25a5 (average fold change of 46.2 and an average P = 0.0318); serpinb3b (average fold change of 35.6 and an average P = 0.0345; serpinB1, human orthologue); and kallikrein related peptidase 6 (average fold change of 4.7 and an average P = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, P < 0.0001), KLK6 (9.0-fold, P = 0.002), stefin A1 (7.3-fold; P < 0.001) and slc25A5 (1.5-fold; P = 0.05) using qRT-PCR on a second cohort of animals (n=8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; P < 0.05), 29,000-fold (stefinA1; P < 0.01), 322-fold (KLK6; P < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes vs. healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3.0-fold), KLK6 (5.8-fold) and serpinB1 (76-fold; all P < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover slc25a5, cystatin A, KLK6 and serpinB1 protein were all increased in lesional psoriasis skin compared to normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of auto-antigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments.

Dataset Information

Proteomic investigations of human HERC2 mutants: insights into the pathobiology of a neurodevelopmental disorder

Publications

Proteomic investigations of human HERC2 mutants: Insights into the pathobiology of a neurodevelopmental disorder.

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