TY - JOUR
T1 - TBK-1 Promotes Autophagy-Mediated Antimicrobial Defense by Controlling Autophagosome Maturation
AU - Pilli, Manohar
AU - Arko-Mensah, John
AU - Ponpuak, Marisa
AU - Roberts, Esteban
AU - Master, Sharon
AU - Mandell, Michael A.
AU - Dupont, Nicolas
AU - Ornatowski, Wojciech
AU - Jiang, Shanya
AU - Bradfute, Steven B.
AU - Bruun, Jack Ansgar
AU - Hansen, Tom Egil
AU - Johansen, Terje
AU - Deretic, Vojo
PY - 2012/8/24
Y1 - 2012/8/24
N2 - Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here, we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key proinflammatory cytokine, IL-1β, induced autophagy leading to autophagic killing of mycobacteria in macrophages, and this IL-1β activity was dependent on TBK-1. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles.
AB - Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here, we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key proinflammatory cytokine, IL-1β, induced autophagy leading to autophagic killing of mycobacteria in macrophages, and this IL-1β activity was dependent on TBK-1. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles.
UR - http://www.scopus.com/inward/record.url?scp=84865357562&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2012.04.015
DO - 10.1016/j.immuni.2012.04.015
M3 - Article
C2 - 22921120
AN - SCOPUS:84865357562
SN - 1074-7613
VL - 37
SP - 223
EP - 234
JO - Immunity
JF - Immunity
IS - 2
ER -
