Delivery of Cytosolic Components by Autophagic Adaptor Protein p62 Endows Autophagosomes with Unique Antimicrobial Properties

• Published in: Immunity (Cambridge, Mass.) Vol. 32; no. 3; pp. 329 - 341
• Main Authors: Ponpuak, Marisa, Davis, Alexander S., Roberts, Esteban A., Delgado, Monica A., Dinkins, Christina, Zhao, Zijiang, Virgin, Herbert W., Kyei, George B., Johansen, Terje, Vergne, Isabelle, Deretic, Vojo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.03.2010; Elsevier Limited
• Subjects: Acidification; Adaptor Proteins, Signal Transducing - immunology; Animals; Antimicrobial agents; Autophagy; Biological Transport; Cells, Cultured; Cytosol - immunology; Cytosol - metabolism; Heat-Shock Proteins - immunology; Mice; Mice, Inbred C57BL; MOLIMMUNO; Mycobacterium; Mycobacterium tuberculosis - immunology; Phagosomes - immunology; Phagosomes - metabolism; Protein Binding; Proteins; Sequestosome-1 Protein; Ubiquitin - metabolism; MOLIMMUNO
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2010.02.009

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. [Display omitted] ► Autophagy converts specific cytoplasmic proteins into antimicrobial peptides ► Autophagic adaptor p62 delivers Fau and ubiquitinated complexes to autolysosomes ► Ribosomal proteins and ubiquitin are digested by lysosomal hydrolases in autolysosomes ► Conversion of cytoplasmic proteins into bactericidal peptides kills M. tuberculosis