Molecular basis of ubiquitin recognition by the autophagy receptor CALCOCO2.
The autophagy receptor CALCOCO2/NDP52 functions as a bridging adaptor and plays an essential role in the selective autophagic degradation of invading pathogens by specifically recognizing ubiquitin-coated intracellular pathogens and subsequently targeting them to the autophagic machinery; thereby it is required for innate immune defense against a range of infectious pathogens in mammals. However, the mechanistic basis underlying CALCOCO2-mediated specific recognition of ubiqutinated pathogens is still unknown. Here, using biochemical and structural analyses, we demonstrated that the cargo-binding region of CALCOCO2 contains a dynamic unconventional zinc finger as well as a C2H2-type zinc-finger, and only the C2H2-type zinc finger specifically recognizes mono-ubiquitin or poly-ubiquitin chains. In addition to elucidating the specific ubiquitin recognition mechanism of CALCOCO2, the structure of the CALCOCO2 C2H2-type zinc finger in complex with mono-ubiquitin also uncovers a unique zinc finger-binding mode for ubiquitin. Our findings provide mechanistic insight into how CALCOCO2 targets ubiquitin-decorated pathogens for autophagic degradations.
a State Key Laboratory of Bioorganic and Natural Products Chemistry.
Xingqiao
X
Xie
a State Key Laboratory of Bioorganic and Natural Products Chemistry.|b Interdisciplinary Research Center on Biology and Chemistry.
Faxiang
F
Li
d Unit of Pathogenic Fungal Infection and Host Immunity; Institut Pasteur of Shanghai; Chinese Academy of Science ; Shanghai , China.
Yuanyuan
Y
Wang
a State Key Laboratory of Bioorganic and Natural Products Chemistry.
Yingli
Y
Wang
e Division of Life Science, State Key Laboratory of Molecular Neuroscience; Hong Kong University of Science and Technology ; Kowloon , Hong Kong , China.
Zhijie
Z
Lin
a State Key Laboratory of Bioorganic and Natural Products Chemistry.|b Interdisciplinary Research Center on Biology and Chemistry.
Xiaofang
X
Cheng
a State Key Laboratory of Bioorganic and Natural Products Chemistry.
Jianping
J
Liu
d Unit of Pathogenic Fungal Infection and Host Immunity; Institut Pasteur of Shanghai; Chinese Academy of Science ; Shanghai , China.
Changbin
C
Chen
a State Key Laboratory of Bioorganic and Natural Products Chemistry.|c Collaborative Innovation Center of Chemistry for Life Sciences; Shanghai Institute of Organic Chemistry; Chinese Academy of Sciences ; Shanghai , China.
Lifeng
L
Pan
D001343:Autophagy / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D012480:Salmonella Infections / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000302:isolation & purification* / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
C094297:CALCOCO2 protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D025801:Ubiquitin
CALCOCO2/NDP52; autophagy receptor; selective autophagy, ubiquitin-binding zinc finger; xenophagy; zinc finger/ubiquitin complex