ZZ-dependent regulation of p62/SQSTM1 in autophagy

Yi Zhang, Su Ran Mun, Juan F. Linares, JaeWoo Ahn, Christina G. Towers, Chang Hoon Ji, Brent E. Fitzwalter, Michael R. Holden, Wenyi Mi, Xiaobing Shi, Jorge Moscat, Andrew Thorburn, Maria T. Diaz-Meco, Yong Tae Kwon () and Tatiana G. Kutateladze ()
Additional contact information
Yi Zhang: University of Colorado School of Medicine
Su Ran Mun: Seoul National University
Juan F. Linares: Sanford Burnham Prebys Medical Discovery Institute
JaeWoo Ahn: University of Colorado School of Medicine
Christina G. Towers: University of Colorado School of Medicine
Chang Hoon Ji: Seoul National University
Brent E. Fitzwalter: University of Colorado School of Medicine
Michael R. Holden: University of Colorado School of Medicine
Wenyi Mi: Van Andel Research Institute
Xiaobing Shi: Van Andel Research Institute
Jorge Moscat: Sanford Burnham Prebys Medical Discovery Institute
Andrew Thorburn: University of Colorado School of Medicine
Maria T. Diaz-Meco: Sanford Burnham Prebys Medical Discovery Institute
Yong Tae Kwon: Seoul National University
Tatiana G. Kutateladze: University of Colorado School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Autophagic receptor p62 is a critical mediator of cell detoxification, stress response, and metabolic programs and is commonly deregulated in human diseases. The diverse functions of p62 arise from its ability to interact with a large set of ligands, such as arginylated (Nt-R) substrates. Here, we describe the structural mechanism for selective recognition of Nt-R by the ZZ domain of p62 (p62ZZ). We show that binding of p62ZZ to Nt-R substrates stimulates p62 aggregation and macroautophagy and is required for autophagic targeting of p62. p62 is essential for mTORC1 activation in response to arginine, but it is not a direct sensor of free arginine in the mTORC1 pathway. We identified a regulatory linker (RL) region in p62 that binds p62ZZ in vitro and may modulate p62 function. Our findings shed new light on the mechanistic and functional significance of the major cytosolic adaptor protein p62 in two fundamental signaling pathways.

Date: 2018
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DOI: 10.1038/s41467-018-06878-8

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