Dataset Information

SUMO2/3 modification of transcription-associated proteins controls cell viability in response to oxygen and glucose deprivation-mediated stress

ABSTRACT: Because limited oxygen and glucose supply to tissues is a serious challenge that cells must properly measure to decide between surviving or triggering cell death, organisms have developed accurate mechanisms for sensing and signaling these conditions. In recent years, signaling through posttranslational modification of proteins by covalent attachment of the Small Ubiquitin-like Modifier (SUMO) is gaining notoriety about this. Enhanced sumoylation in response to oxygen and glucose deprivation (OGD) constitutes a safeguard mechanism for cells and a new avenue for therapeutic intervention. However, indiscriminate global sumoylation can limit the therapeutic potential that a more precise action on selected targets would have. To clear up this, we have conducted a proteomic approach to identify specific SUMO targets responding to OGD and to investigate the potential these targets and their sumoylation have in preserving cells from death. Proteins undergoing sumoylation in response to OGD are mostly related to transcription and RNA processing, and the majority of them are rapidly desumoylated when restoring oxygen and glucose (ROG), confirming the high dynamism of this modification. Since OGD is highly related to brain ischemia we have also studied a cell line differentiated into neurons. However, no major differences have been observed between the SUMO-proteomes of proliferating and differentiated cells. We show that the overexpression of the transcription factor SOX2 or the SUMO ligase PIAS4 has a manifest cell protective effect largely depending on their sumoylation and that maintaining the sumoylation capacity of the coregulator NAB2 is also important to face OGD. Conversely, the sumoylation of the pluripotency factor OCT4, which is a target for the SUMO protease SENP7 after ROG, seems to block its cell survival-promoting capacity. Thus, better outcomes in cell protection would rely on the appropriate combination of sumoylated and non-sumoylated forms of selected factors.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Román González-Prieto

LAB HEAD: Alfred CO Vertegaal

PROVIDER: PXD056069 | Pride | 2025-05-26

REPOSITORIES: Pride

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SUMO2/3 modification of transcription-associated proteins controls cell viability in response to oxygen and glucose deprivation-mediated stress.

Gallardo-Chamizo Francisco F González-Prieto Román R Jafari Vahid V Luna-Peláez Noelia N Vertegaal Alfred C O ACO García-Domínguez Mario M

Cell death discovery 20250510 1

Because limited oxygen and glucose supply to tissues is a serious challenge that cells must properly measure to decide between surviving or triggering cell death, organisms have developed accurate mechanisms for sensing and signaling these conditions. In recent years, signaling through posttranslational modification of proteins by covalent attachment of the Small Ubiquitin-like Modifier (SUMO) is gaining notoriety. Enhanced sumoylation in response to oxygen and glucose deprivation (OGD) constitu ...[more]

PMID: 40348773

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Project description:Post translational protein modifications (PTMs) including small chemical groups and small proteins, belonging to the ubiquitin family, are essential for virtually all cellular processes. In addition to modification by a single PTM, proteins can be modified by a combination of different modifiers, which are able to influence each other. Since little is known about crosstalk between different ubiquitin family members, we developed an improved method enabling identification of co-modified proteins on a system-wide level using mass spectrometry. We focused on the role of crosstalk between SUMO and ubiquitin during proteasomal degradation. Using two complementary approaches, we identified 498 proteins to be significantly co-modified by SUMO and ubiquitin upon MG132 treatment. These targets included many enzymatic components of PTM machinery, involved in SUMOylation and ubiquitylation, but also phosphorylation, methylation and acetylation, revealing a highly complex interconnected network of crosstalk between different PTMs. In addition various other biological processes were found to be significantly enriched within the group of co-modified proteins, including transcription, DNA repair and the cell cycle. Interestingly, the latter group mostly consisted of proteins involved in mitosis, including a subset of chromosome segregation regulators. We hypothesize that group modification by SUMO-targeted ubiquitin ligases regulates the stability of the identified subset of mitotic proteins, which ensures proper chromosome segregation. The mitotic regulators KIF23 and MIS18BP1 were verified to be co-modified by SUMO and ubiquitin upon inhibition of the proteasome and subsequently identified as novel RNF4 targets. Both modifications on MIS18BP1 were observed to increase simultaneously during late mitosis, while the total protein level decreased immediately afterwards. These results confirm the regulation of MIS18BP1 via SUMO-ubiquitin crosstalk during mitosis. Combined, our work highlights extensive crosstalk between SUMO and ubiquitin, providing a resource for further unraveling of SUMO-ubiquitin crosstalk.

			Action	DRS
	MOUSE.fasta	Fasta
	MaxQuant_1.5.5.1.zip	Other
	mqpar-differentiated.xml	Xml
	mqpar-nondif.xml	Xml
	q103214a.raw	Raw