title: A CREB3-ARF4 signalling pathway mediates the response to Golgi stress and susceptibility to pathogens.
abstract: Treatment of cells with brefeldin A (BFA) blocks secretory vesicle transport and causes a collapse of the Golgi apparatus. To gain more insight into the cellular mechanisms mediating BFA toxicity, we conducted a genome-wide haploid genetic screen that led to the identification of the small G protein ADP-ribosylation factor 4 (ARF4). ARF4 depletion preserves viability, Golgi integrity and cargo trafficking in the presence of BFA, and these effects depend on the guanine nucleotide exchange factor GBF1 and other ARF isoforms including ARF1 and ARF5. ARF4 knockdown cells show increased resistance to several human pathogens including Chlamydia trachomatis and Shigella flexneri. Furthermore, ARF4 expression is induced when cells are exposed to several Golgi-disturbing agents and requires the CREB3 (also known as Luman or LZIP) transcription factor, whose downregulation mimics ARF4 loss. Thus, we have uncovered a CREB3-ARF4 signalling cascade that may be part of a Golgi stress response set in motion by stimuli compromising Golgi capacity.
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Massachusetts Institute of Technology (MIT), Department of Biology, Cambridge, Massachusetts 02142, USA [3] Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4].
authors.forename: Jan H
authors.initials: JH
authors.lastname: Reiling
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Olive
authors.forename: Sumana
authors.initials: S
authors.lastname: Sanyal
authors.forename: Jan E
authors.initials: JE
authors.lastname: Carette
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.forename: Michael N
authors.initials: MN
authors.lastname: Starnbach
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D020126:Brefeldin A / Q000494:pharmacology; D002692:Chlamydia trachomatis / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004198:Disease Susceptibility; D055785:Gene Knockdown Techniques; D006056:Golgi Apparatus / Q000187:drug effects / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D012763:Shigella flexneri / Q000502:physiology; D015398:Signal Transduction; D013312:Stress, Physiological; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C107941:CREB3 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C120445:GBF1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; D020126:Brefeldin A; D020823:ADP-Ribosylation Factor 1; D020727:ADP-Ribosylation Factors; C116688:ARF4 protein, human