Activation of the unfolded protein response by Listeria monocytogenes.
The endoplasmic reticulum (ER) responds to perturbation of homeostasis with stress. To maintain ER function, a signalling-circuitry has evolved which, when engaged, attempts to reduce a surplus of unfolded proteins by triggering the unfolded protein response (UPR). Several studies have implicated UPR in viral infections, neurodegenerative disorders and metabolic diseases but UPR has not yet been widely linked to bacterial infections. Here we demonstrate that the facultative intracellular pathogen Listeria monocytogenes (Lm) induces ER expansion and UPR prior to host cell entry. Lm activated protein kinase RNA-like ER kinase (PERK) evidenced by the phosphorylation of the α-subunit of eukaryotic translation initiation factor-2 (eIF2α), inositol-requiring protein-1 (IRE1) as shown by detection of spliced X-box binding protein-1 (XBP1) and activating transcription factor-6 (ATF6) as demonstrated by depletion of its inactive form. A mutant LmΔhly strain that did not produce listeriolysin (LLO) lacked the UPR response. Conversely purified LLO activated UPR. Sustained infection with Lm resulted in apoptosis. Induction of ER stress by thapsigargin or tunicamycin reduced intracellular bacterial number. Our findings suggest that UPR plays an important role in the cell autonomous defence responses to bacterial infection.
Institute of Medical Microbiology, Justus-Liebig-University, D-35392 Giessen, Germany.
Helena
H
Pillich
Maria
M
Loose
Klaus-Peter
KP
Zimmer
Trinad
T
Chakraborty
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology; D006460:Hemolysin Proteins / Q000378:metabolism / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000276:immunology / Q000502:physiology*; D051379:Mice; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1
D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D001427:Bacterial Toxins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D014415:Tunicamycin; D019284:Thapsigargin; D011393:Procollagen-Proline Dioxygenase; C526500:P4hb protein, mouse; D019704:Protein Disulfide-Isomerases; C038705:hlyA protein, Listeria monocytogenes; D002118:Calcium