title: Novel role of Wag31 in protection of mycobacteria under oxidative stress.
abstract: Wag31 of Mycobacterium tuberculosis belongs to the DivIVA family of proteins known to regulate cell morphology in Gram-positive bacteria. Here we demonstrate an unrecognized, novel role of Wag31 in oxidatively stressed mycobacteria. We report the cleavage of penicillin-binding protein 3 (PBP3) by the intramembrane metalloprotease Rv2869c (MSMEG_2579) in oxidatively stressed cells. Amino acids (102)A and (103)A of PBP3 are required for Rv2869c-mediated cleavage. Wag31(MTB), by virtue of its interaction with PBP3 through amino acid residues (46)NSD(48), protects it from oxidative stress-induced cleavage. PBP3 undergoes cleavage in Mycobacterium smegmatis (strain PM2) harbouring wag31(Delta(46)NSD(48)) instead of the wild type, with concomitant reduction in ability to withstand oxidative stress. Overexpression of Wag31(Delta(46)NSD(48)) attenuates the survival of M. tuberculosis in macrophages with concomitant cleavage of PBP3, and renders the organism more susceptible towards hydrogen peroxide as well as drugs which generate reactive oxygen species, namely isoniazid and ofloxacin. We propose that targeting Wag31 could enhance the activity of mycobactericidal drugs which are known to generate reactive oxygen species.
authors.affiliation: Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra, Road, Kolkata 700009, India.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukherjee
authors.forename: Kamakshi
authors.initials: K
authors.lastname: Sureka
authors.forename: Pratik
authors.initials: P
authors.lastname: Datta
authors.forename: Tofajjen
authors.initials: T
authors.lastname: Hossain
authors.forename: Subhasis
authors.initials: S
authors.lastname: Barik
authors.forename: Kali P
authors.initials: KP
authors.lastname: Das
authors.forename: Manikuntala
authors.initials: M
authors.lastname: Kundu
authors.forename: Joyoti
authors.initials: J
authors.lastname: Basu
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004269:DNA, Bacterial / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D020102:Mycobacterium smegmatis / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D046915:Penicillin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D046915:Penicillin-Binding Proteins; D017382:Reactive Oxygen Species