title: Delivery of cytosolic components by autophagic adaptor protein p62 endows autophagosomes with unique antimicrobial properties.
abstract: Autophagy allows cells to self-digest portions of their own cytoplasm for a multitude of physiological purposes, including innate and adaptive immunity functions. In one of its innate immunity manifestations, autophagy, is known to contribute to the killing of intracellular microbes, including Mycobacterium tuberculosis, although the molecular mechanisms have been unclear. Here, we delineated sequential steps of the autophagic pathway necessary to control intracellular M. tuberculosis and found that in addition to autophagy initiation and maturation, an accessory autophagy-targeting molecule p62 (A170 or SQSTM1) was required for mycobactericidal activity. The p62 adaptor protein delivered specific ribosomal and bulk ubiquitinated cytosolic proteins to autolysosomes where they were proteolytically converted into products capable of killing M. tuberculosis. Thus, p62 brings cytosolic proteins to autolysosomes where they are processed from innocuous precursors into neo-antimicrobial peptides, explaining in part the unique bactericidal properties of autophagic organelles.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Ponpuak
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Davis
authors.forename: Esteban A
authors.initials: EA
authors.lastname: Roberts
authors.forename: Monica A
authors.initials: MA
authors.lastname: Delgado
authors.forename: Christina
authors.initials: C
authors.lastname: Dinkins
authors.forename: Zijiang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: George B
authors.initials: GB
authors.lastname: Kyei
authors.forename: Terje
authors.initials: T
authors.lastname: Johansen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vergne
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D001343:Autophagy; D001692:Biological Transport; D002478:Cells, Cultured; D003600:Cytosol / Q000276:immunology* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin