Golgi stress-induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing

• Published in: Molecular biology of the cell 2018-01, Vol.29 (1), p.42-52
• Main Authors: Baumann, Jan, Ignashkova, Tatiana I, Chirasani, Sridhar R, Ramírez-Peinado, Silvia, Alborzinia, Hamed, Gendarme, Mathieu, Kuhnigk, Kyra, Kramer, Valentin, Lindemann, Ralph K, Reiling, Jan H
• Format: Article
• Language: English
• Subjects: A549 Cells; Alternative Splicing - drug effects; Alternative Splicing - genetics; Apoptosis - drug effects; Brefeldin A - pharmacology; Cytoprotection - drug effects; Gene Expression Profiling; Gene Knockdown Techniques; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; HEK293 Cells; HeLa Cells; Humans; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinases - metabolism; Monensin - pharmacology; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Proto-Oncogene Proteins c-ets - metabolism; Pyridines - pharmacology; Quinolines - pharmacology; Small Molecule Libraries - pharmacology; Spliceosomes - drug effects; Spliceosomes - metabolism; Stress, Physiological - drug effects; Transcription, Genetic - drug effects; Transcriptome - drug effects; Transcriptome - genetics; Up-Regulation - drug effects
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E17-06-0418

The secretory pathway is a major determinant of cellular homoeostasis. While research into secretory stress signaling has so far mostly focused on the endoplasmic reticulum (ER), emerging data suggest that the Golgi itself serves as an important signaling hub capable of initiating stress responses. To systematically identify novel Golgi stress mediators, we performed a transcriptomic analysis of cells exposed to three different pharmacological compounds known to elicit Golgi fragmentation: brefeldin A, golgicide A, and monensin. Subsequent gene-set enrichment analysis revealed a significant contribution of the ETS family transcription factors ELK1, GABPA/B, and ETS1 to the control of gene expression following compound treatment. Induction of Golgi stress leads to a late activation of the ETS upstream kinases MEK1/2 and ERK1/2, resulting in enhanced ETS factor activity and the transcription of ETS family target genes related to spliceosome function and cell death induction via alternate MCL1 splicing. Further genetic analyses using loss-of-function and gain-of-function experiments suggest that these transcription factors operate in parallel.