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Global proteome remodeling during ER stress involves Hac1-driven expression of long undecoded transcript isoforms

ABSTRACT: Cellular stress response pathways often require transcription-based activation of gene expression to promote cellular adaptation. However, whether general mechanisms exist for stress-responsive gene down-regulation is less clear. A recently defined gene regulatory mechanism enables both up- and down-regulation of protein levels for distinct gene sets by the same transcription factor (TF) via coordinated induction of canonical mRNAs and long undecoded transcript isoforms (LUTIs). We analyzed deep, parallel gene expression datasets to determine whether this mechanism contributes to the conserved Hac1-driven branch of the unfolded protein response (UPRER). Indeed, we found Hac1-dependent protein down-regulation that accompanied the well-characterized up-regulation of ER-related proteins that typifies UPRER activation. Proteins down-regulated by Hac1-driven LUTIs include those with electron transport chain (ETC) function. Aerobic respiration also appears dampened during the UPRER, and abrogated ETC function improves the fitness of UPRER-activated cells, suggesting functional importance of LUTI regulation during the UPRER. We conclude that the UPRER involves large-scale proteome remodeling, mediated in part by Hac1-induced LUTIs, and that this mechanism enables coordination of up- and down-regulation of gene expression during this stress response.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE115366 | GEO | 2018/08/26

REPOSITORIES: GEO

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Project description:Heat stress (HS) could damage animal reproduction, while the mechanisms are still required to be better understood. Here, we showed that incubation of porcine immature Sertoli cells (iSCs) at 43 °C for 30 minutes followed 36h recovery under normal culture could inhibit the proliferation, promote apoptosis and increase the lactate production. Then, we profiled mRNA expression by RNA sequencing on Control (before HS), HS0.5 (0h after HS) and HS0.5-R36 (36h recovery after HS) groups of iSCs. We identified 126 (92 up- and 64 down-regulated), 3372 (2076 up- and 1296 down-regulated) and 3096 (1772 up- and 1324 down-regulated) differentially expressed (DE) mRNAs respectively in HS0 vs. Control, HS0-R36 vs. HS0 and HS0-R36 vs. Control comparisons. Gene ontology (GO ) enrichment found multiple significantly enriched biological pathways involved in different comparisons, including cellular response to heat, heat shock protein binding, regulation of cellular response to stress, RNA polyadenylation, sterol biosynthetic process, positive regulation of stress-activated MAPK cascade, chaperone-mediated protein folding, ATPase activity, cell cycle process and DNA replication etc. KEGG analysis showed the changed pathways, including cell cycle, MAPK, P53, PI3K-AKT, GnRH, HIF1, Wnt, cAMP signal pathways and Glycolysis/Gluconeogenesis etc. RT-qPCR validation of 9 DEGs (DNAJB1, TRAF6, INSIG1, GADD45G, HDAC6, FKBP4, SERPINE1, PFKP and GALM) showed the expression change trend of most DEGs (except TRAF6) consistent with the RNA-seq. Moreover, 6 of HSPs (HSPA6, HSPB1, HSPD1, HSP90AA1, HSP90AB1 and HSPH1) were validated by RT-qPCR and 5 of 6 (except HSP90AB1) showed the similar expression trend to RNA-seq results. Further validation of HSP90AA1 on protein level via immunostaining and westernbloting showed similar expression trend to RT-qPCR and RNA-seq. Taken together, HS could extensively change the global transcriptome, especially HSPs, to affect proliferation, apoptosis and metabolite production of pig iSCs.

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Global proteome remodeling during ER stress involves Hac1-driven expression of long undecoded transcript isoforms

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