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dc.creatorMesquita, FS-
dc.creatorBrito, C-
dc.creatorMazon, Moya MJ-
dc.creatorPinheiro, JC-
dc.creatorMostowy, S-
dc.creatorCabanes, D-
dc.creatorSousa, S-
dc.description.abstractDuring 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.-
dc.description.sponsorshipWe are grateful to M.T. Almeida and M. Martins who made preliminary observations on the Gp96-NMHCIIA interaction. We are thankful to P. Cossart from Institut Pasteur, Paris, France; O.V. Vieira from CEDOC, Nova Medical School Lisbon, Portugal; and G. Van der Goot from Ecole Polytechnique Federale de Lausanne, Switzerland, for the kind gift of purified LLO, SLO and aerolysin, respectively. We thank C. Leitao (AFCU), P. Sampaio (ALM) and R. Fernandes (HEMS) from IBMC facilities for technical assistance and J. Bessa and J. Marques for guidance in zebrafish experiments. This work was supported by national funds through FCT-Fundacao para a Ciencia e a Tecnologia/MEC-Ministerio da Educacao e Ciencia and co-funded by Fundo Europeu de Desenvolvimento Regional (FEDER) within the partnership agreement PT2020 related to the research unit number 4293 and through the Operational Competitiveness Programme (COMPETE) under the project "NORTE-07-0124-FEDER-000002-Host-Pathogen Interactions" co-funded by Programa Operacional Regional do Norte (ON.2-O Novo Norte), under the Quadro de Referencia Estrategico Nacional (QREN), through the FEDER and by FCT. It also received support from a Research Grant 2014 by European Society of Clinical Microbiology and Infectious Diseases (ESCMID) (to SS) and from PT2020 research project Infect-ERA/0001/2013 PROANTILIS. Work in the SM Laboratory is supported by a Wellcome Trust Research Career Development Fellowship (WT097411MA) and the Lister Institute of Preventive Medicine. FSM was funded through an EMBO Long-term Postdoctoral Fellowship (EMBO ALTF 864-2012) and a FCT Post-Doctoral Fellowship (SFRH/BPD/94458/2013) through FCT/MEC co-funded by QREN and POPH (Programa Operacional Potencial Humano). CB and JCP received FCT Doctoral Fellowships (SFRH/BD/112217/2015 and SFRH/BD/86871/2012, respectively). SS was supported by FCT Investigator Programme (COMPETE, POPH and FCT).-
dc.relation.ispartofEMBO Reports, vol. 18(2) p. 303-318-
dc.subjectBacterial Proteins/metabolism-
dc.subjectBacterial Toxins/metabolism-
dc.subjectCell Survival-
dc.subjectListeria monocytogenes-
dc.subjectMembrane Glycoproteins/metabolism-
dc.subjectMolecular Chaperones/metabolism-
dc.subjectPore Forming Cytotoxic Proteins/metabolism-
dc.titleEndoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore-forming toxins-
dc.typeArtigo em Revista Científica Internacional-
dc.contributor.uportoInstituto de Investigação e Inovação em Saúde-
Appears in Collections:I3S - Artigo em Revista Científica Internacional

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