title: The globally disseminated M1T1 clone of group A Streptococcus evades autophagy for intracellular replication.
abstract: Autophagy is reported to be an important innate immune defense against the intracellular bacterial pathogen Group A Streptococcus (GAS). However, the GAS strains examined to date belong to serotypes infrequently associated with human disease. We find that the globally disseminated serotype M1T1 clone of GAS can evade autophagy and replicate efficiently in the cytosol of infected cells. Cytosolic M1T1 GAS (strain 5448), but not M6 GAS (strain JRS4), avoids ubiquitylation and recognition by the host autophagy marker LC3 and ubiquitin-LC3 adaptor proteins NDP52, p62, and NBR1. Expression of SpeB, a streptococcal cysteine protease, is critical for this process, as an isogenic M1T1 ΔspeB mutant is targeted to autophagy and attenuated for intracellular replication. SpeB degrades p62, NDP52, and NBR1 in vitro and within the host cell cytosol. These results uncover a proteolytic mechanism utilized by GAS to escape the host autophagy pathway that may underpin the success of the M1T1 clone.
authors: Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia.
authors: Timothy C
authors: TC
authors: Barnett
authors: Institute for Molecular Bioscience, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia.
authors: David
authors: D
authors: Liebl
authors: Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia.
authors: Lisa M
authors: LM
authors: Seymour
authors: Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia.
authors: Christine M
authors: CM
authors: Gillen
authors: Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia.
authors: Jin Yan
authors: JY
authors: Lim
authors: Department of Pediatrics and Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Christopher N
authors: CN
authors: Larock
authors: Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors: Mark R
authors: MR
authors: Davies
authors: Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia.
authors: Benjamin L
authors: BL
authors: Schulz
authors: Department of Pediatrics and Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Victor
authors: V
authors: Nizet
authors: Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia; Institute for Molecular Bioscience, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia.
authors: Rohan D
authors: RD
authors: Teasdale
authors: Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, St Lucia, QLD 4072, Australia. Electronic address: mark.walker@uq.edu.au.
authors: Mark J
authors: MJ
authors: Walker
mesh_terms: D001343:Autophagy; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000382:microbiology; D005098:Exotoxins / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D013297:Streptococcus pyogenes / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology*; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D005098:Exotoxins; D037521:Virulence Factors; C027951:erythrogenic toxin