title: EccA1, a component of the Mycobacterium marinum ESX-1 protein virulence factor secretion pathway, regulates mycolic acid lipid synthesis.
abstract: Pathogenic mycobacteria, which cause multiple diseases including tuberculosis, secrete factors essential for disease via the ESX-1 protein export system and are partially protected from host defenses by their lipid-rich cell envelopes. These pathogenic features of mycobacterial biology are believed to act independently of each other. Key ESX-1 components include three ATPases, and EccA1 (Mycobacterium marinum MMAR_5443; M. tuberculosis Rv3868) is the least characterized. Here we show that M. marinum EccA1's ATPase activity is required for ESX-1-mediated protein secretion, and surprisingly for the optimal synthesis of mycolic acids, integral cell-envelope lipids. Increased mycolic acid synthesis defects, observed when an EccA1-ATPase mutant is expressed in an eccA1-null strain, correlate with decreased in vivo virulence and intracellular growth. These data suggest that two mycobacterial virulence hallmarks, ESX-1-dependent protein secretion and mycolic acid synthesis, are critically linked via EccA1.
authors.affiliation: Department of Microbial Pathogenesis, Genentech, South San Francisco, CA 94080, USA. sajoshi@stanford.edu
authors.forename: Shilpa A
authors.initials: SA
authors.lastname: Joshi
authors.forename: David A
authors.initials: DA
authors.lastname: Ball
authors.forename: Mei G
authors.initials: MG
authors.lastname: Sun
authors.forename: Fredric
authors.initials: F
authors.lastname: Carlsson
authors.forename: Brigitte Y
authors.initials: BY
authors.lastname: Watkins
authors.forename: Nina
authors.initials: N
authors.lastname: Aggarwal
authors.forename: Jenna M
authors.initials: JM
authors.lastname: McCracken
authors.forename: Kassidy K
authors.initials: KK
authors.lastname: Huynh
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis*; D008958:Models, Molecular; D019910:Mycobacterium marinum / Q000201:enzymology / Q000378:metabolism*; D009171:Mycolic Acids / Q000378:metabolism*; D055571:Secretory Pathway; D037521:Virulence Factors / Q000378:metabolism; D015027:Zebrafish
chemical_list: D001426:Bacterial Proteins; D008055:Lipids; D009171:Mycolic Acids; D037521:Virulence Factors; D000251:Adenosine Triphosphatases