Poster Presentation HUPO 2019 - 18th Human Proteome Organization World Congress

Differential oxidation of protein tyrosine phosphatases in metabolic diseases (#925)

Julia Bauza-Martinez 1 , Giuseppe Sammarco 1 , Esteban N Gurzov 2 , Wei Wu 1
  1. Utrecht University, Utrecht, UTRECHT, Netherlands
  2. ULB Center for Diabetes Research, Universite Libre de Bruxelles, Brussels, Belgium

Protein tyrosine phosphatases (PTPs) are a class of enzymes that attenuate phospho-tyrosine signaling. In various metabolic diseases, sustained dysregulation of insulin and leptin phosphorylation signaling have been reported, which may be corrected by PTP activity. While metabolic diseases are generally associated with an oxidative tissue environment that could oxidise (and thus inactivate) PTPs, the redox status of individual PTPs in disease settings are still largely unknown. Using a highly sensitive and robust AP-MS workflow, we have previously detected PTP oxidations (oxPTPs) in live zebrafish within 40 min of tail-fin amputation, and validated that the specific oxidation of PTPN11 in this time window is critical to initiate tissue regeneration. Due to high catalytic site sequence conservation between different PTPs and across organisms, collective enrichment and analysis of oxidized PTP active sites is feasible by AP-MS.

In this work, we streamlined the strategy to support oxPTP profiling from animal tissue and extremely limited needle-biopsies from patients, in the contexts of obesity and diabetes, as well as fatty liver and associated steatotic-inflammatory diseases. We show here that (i) high fat diet in mice induced specific PTP oxidations in a manner independent of liver tissue PTP expression, (ii) a unique oxPTP subset correlates with curative responsiveness in diabetic reversal by a novel combination therapy, and that (iii) distinct oxPTP profiles were detected in fatty/fibrotic livers compared to healthy human livers. The unifying oxPTP hits in these datasets may provide leads to understand the origin and bases for predisposition and co-morbidities across these metabolic conditions, and hint at novel mechanistic routes that prevent high BMI from progressing into metabolic disease.