Delivery of cytosolic components by autophagic adaptor protein p62 endows autophagosomes with unique antimicrobial properties.
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.
Ponpuak
Marisa
M
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Davis
Alexander S
AS
Roberts
Esteban A
EA
Delgado
Monica A
MA
Dinkins
Christina
C
Zhao
Zijiang
Z
Virgin
Herbert W
HW
Kyei
George B
GB
Johansen
Terje
T
Vergne
Isabelle
I
Deretic
Vojo
V
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
D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin