title: Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore-forming toxins.
abstract: During infection, plasma membrane (PM) blebs protect host cells against bacterial pore-forming toxins (PFTs), but were also proposed to promote pathogen dissemination. However, the details and impact of blebbing regulation during infection remained unclear. Here, we identify the endoplasmic reticulum chaperone Gp96 as a novel regulator of PFT-induced blebbing. Gp96 interacts with non-muscle myosin heavy chain IIA (NMHCIIA) and controls its activity and remodelling, which is required for appropriate coordination of bleb formation and retraction. This mechanism involves NMHCIIA-Gp96 interaction and their recruitment to PM blebs and strongly resembles retraction of uropod-like structures from polarized migrating cells, a process that also promotes NMHCIIA-Gp96 association. Consistently, Gp96 and NMHCIIA not only protect the PM integrity from listeriolysin O (LLO) during infection by Listeria monocytogenes but also affect cytoskeletal organization and cell migration. Finally, we validate the association between Gp96 and NMHCIIA in vivo and show that Gp96 is required to protect hosts from LLO-dependent killing.
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Group of Molecular Microbiology, IBMC, Universidade do Porto, Porto, Portugal.
authors.forename: Francisco Sarmento
authors.initials: FS
authors.lastname: Mesquita
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Group of Molecular Microbiology, IBMC, Universidade do Porto, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Brito
authors.affiliation: Section of Microbiology, MRC Centre for Molecular Bacteriology and Infection (CMBI), Imperial College London, London, UK.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Mazon Moya
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Group of Molecular Microbiology, IBMC, Universidade do Porto, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Jorge Campos
authors.initials: JC
authors.lastname: Pinheiro
authors.affiliation: Section of Microbiology, MRC Centre for Molecular Bacteriology and Infection (CMBI), Imperial College London, London, UK.
authors.forename: Serge
authors.identifier: 0000-0002-7286-6503
authors.initials: S
authors.lastname: Mostowy
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal didier@ibmc.up.pt srsousa@ibmc.up.pt.|Group of Molecular Microbiology, IBMC, Universidade do Porto, Porto, Portugal.
authors.forename: Didier
authors.initials: D
authors.lastname: Cabanes
authors.affiliation: I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal didier@ibmc.up.pt srsousa@ibmc.up.pt.|Group of Molecular Microbiology, IBMC, Universidade do Porto, Porto, Portugal.
authors.forename: Sandra
authors.identifier: 0000-0001-8578-0461
authors.initials: S
authors.lastname: Sousa
mesh_terms: D000205:Actomyosin / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism*; D002470:Cell Survival; D006801:Humans; D008089:Listeria monocytogenes; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D052899:Pore Forming Cytotoxic Proteins; C053387:endoplasmin; D000205:Actomyosin
keywords: 
  Listeria monocytogenes
  ; actomyosin; endoplasmic reticulum chaperone; plasma membrane blebbing; pore‐forming toxins