Hypoxia-induced Changes in SUMO Conjugation Affect Transcriptional Regulation Under Low Oxygen

Abstract

HeLa cells grown under normoxia or hypoxia for 48h, were subjected to endogenous SUMO-immunoprecipitation in combination with quantitative mass spectrometry (SILAC) to gain insights into differences of the SUMO1 and SUMO2/3 proteome. Proteins whose SUMOylation changed without concomitant change in abundance were predominantly transcriptions factors. Particularly interesting was transcription factor TFAP2A (Activating enhancer binding Protein 2 alpha), whose sumoylation decreased on hypoxia. DeSUMOylation of TFAP2A enhanced transcriptional activity of HIF-1 under hypoxia contributing at the cellular response to low oxygen.

The Role of Sumoylation in the Response to Hypoxia: An Overview

“…By using a SILAC-quantitative proteomic approach, we did not observe a massive increase in the number of SUMO1 or SUMO2/3 modified proteins but rather significant sumoylation-status changes of a small group of proteins [103]. These proteins were mostly transcription factors (like TFAP2a, a protein that could be involved in the hypoxic response [103]). Kunz et al [102] also identified alteration in sumoylation in a subset of proteins, such as the SUMO machinery enzymes RanBP2 and PIAS2 E3 SUMO ligases and regulators of transcription, by analyzing normoxic and hypoxic cells using comparative mass spectrometry.…”

“…Increased global SUMO-conjugation upon hypoxia was initially reported as a result of increased SUMO1 expression in T84 colon cells cultured under hypoxia and in the brain and heart of mice exposed to 10% oxygen [100,101]. Others and we have investigated the SUMO proteome of cells that have been kept for 24-48 h under the hypoxic condition (1% oxygen) [102,103]. By using a SILAC-quantitative proteomic approach, we did not observe a massive increase in the number of SUMO1 or SUMO2/3 modified proteins but rather significant sumoylation-status changes of a small group of proteins [103].…”

“…Others and we have investigated the SUMO proteome of cells that have been kept for 24-48 h under the hypoxic condition (1% oxygen) [102,103]. By using a SILAC-quantitative proteomic approach, we did not observe a massive increase in the number of SUMO1 or SUMO2/3 modified proteins but rather significant sumoylation-status changes of a small group of proteins [103]. These proteins were mostly transcription factors (like TFAP2a, a protein that could be involved in the hypoxic response [103]).…”

Roles Of HIF and 2-Oxoglutarate Dependent Enzymes in Controlling Gene Expression In Hypoxia

“…Proteomics approaches revealed hypoxia induces changes to many post translational modifications (PTMs) on non-histone proteins, such as proline hydroxylation [80,81](regulating protein levels and interactions), phosphorylation [82,83], SUMOylation [84], acetylation [85], glycosylation [86], nitration [87]and nitrosylation [88](all of which regulate protein functions in different ways).…”

“…The deSUMOylation of Transcription Factor AP-2 Alpha (TFAP2A), which is known to interact with HIF-1, could enhance the transcriptional activity of HIF-1 under hypoxic conditions [84]. Hypoxia could increase the NAD+-sensitive Sirtuin 3 (SIRT3) activity, that deacetylates key metabolic enzymes and significantly changes the acetylation pattern within the mitochondria.…”