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MHCI peptidome of HepG2 with ArgRS or SRRM2 knock down

ABSTRACT: Cells need to sense and respond adequately to environmental stimuli. Metabolites provide information on systemic changes, for example during inflammation. We show that depletion of the amino acid arginine during inflammation reduced nuclear levels of its cognate aminoacyl tRNA synthetase, Arginyl-tRNA synthetase (ArgRS). In the nucleus, ArgRS interacted with serine/arginine repetitive matrix protein 2 (SRRM2), a spliceosomal protein and nuclear speckle organizer, in distinct condensate-like structures. ArgRS’ presence in the nucleus impeded SRRM2 mobility. Differences in SRRM2 speckle trafficking were directly reflected in alternative mRNA splicing: splice site usage was regulated in the opposite direction by ArgRS as by SRRM2, suggesting sequestration of SRRM2 by ArgRS as a regulatory mechanism. ArgRS- and SRRM2-dependent mRNA processing changes cumulated in altered metabolism and peptide presentation to immune cells. Our findings indicate a general mechanism in which ArgRS and SRRM2 act together as upstream regulators during the physiological response to inflammatory injury.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Cell Culture

DISEASE(S): Liver Cancer

SUBMITTER: Haissi Cui

LAB HEAD: Paul Schimmel

PROVIDER: PXD027531 | Pride | 2025-06-12

REPOSITORIES: Pride

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Project description:Aims/hypothesis AGEs are considered environmental contributors of type 1 diabetes, but the exact role AGEs play early in pathogenesis of the disease, remains unidentified. We aimed to reduce AGEs with the pharmacotherapy alagebrium chloride in MIN6N8 cells and early in life in NOD mice to determine its impact on beta cell immunogenicity, function, and disease progression. Methods MIN6N8 cells were cultured with AGEs with or without short-term alagebrium therapy to determine the effect on ER stress and beta cell antigen presentation via a reporter assay for protein responses in the unfolded protein response, the enzymatic activity of endoplasmic reticulum aminopeptidase-1 (ERAP1) and the immunopeptidome. To determine the effect of short-term alagebrium therapy on beta cells in vivo, female NOD mice were treated with alagebrium and insulin secretion, insulitis, and immune cell repertoire were studied. Adoptive transfer studies and diabetes progression studies were used to consider the impact of alagebrium on immune cell function and disease outcome. Results In MIN6N8 cells, alagebrium therapy inhibited the induction of endoplasmic reticulum (ER) stress and the activity of ERAP1 by AGE-modified proteins. Alagebrium treated-MIN6N8 cells did not change the MHC Class I presentation of known beta cell antigens but did induce proteomic changes related to ER homeostatic pathways. Prior to overt autoimmune diabetes, female NOD mice treated with alagebrium for 30-40 days had improved insulin secretion, reduced insulitis and amplified proportions of pancreatic CD8+ T cells, mature B cells and F4/80+ macrophages. Splenocytes from alagebrium-treated mice adoptively transferred disease to NODscid recipients and maintained interferon production in vitro. While partial protection of islets by alagebrium was seen following the adoptive transfer of activated NOD G9C8 transgenic TCR CD8+ T cells, alagebrium therapy in NOD mice did not reduce diabetes progression. Conclusions/interpretation Our data suggests that in experimental models of diabetes, short-term alagebrium treatment allows for beta cell improvement, and maintenance of immune cell function, which does not fully mitigate diabetes progression.

			Action	DRS
	20210619_PSHC-100.ms2	Other
	20210619_PSHC-100.mzXML	Mzxml
	20210619_PSHC-100.raw	Raw
	20210619_PSHC-101.ms2	Other
	20210619_PSHC-101.mzXML	Mzxml

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MHCI peptidome of HepG2 with ArgRS or SRRM2 knock down

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