ZZ-dependent regulation of p62/SQSTM1 in autophagy

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.

Disrupting the LC3 Interaction Region (LIR) Binding of Selective Autophagy Receptors Sensitizes AML Cell Lines to Cytarabine

“…(A) OPTN, p62 and NDP52 are multifunctional proteins that contain domains mediating multimerization (blue) and cargo recognition (green). In p62, the ZZ domain (orange) binds arginylated (Nt-R) substrates (Zhang et al, 2018). The SKICH domain (magenta) of NDP52 has been shown to bind to intracellular membranes (Von Muhlinen et al, 2012).…”

Discovery of Novel Autophagy Inhibitors and Their Sensitization Abilities for Vincristine‐Resistant Esophageal Cancer Cell Line Eca109/VCR

“…In an effort to elucidate the interaction of p62‐zz domain and 4 d , Surflex‐Dock GeomX module in SYBYL‐X 2.0 was carried out, based on the newly resolved structure of p62‐zz domain (PDB ID: 6MJ7). In brief, 4 d as well as reported p62‐zz domain ligands XIE62‐1004 and XIE2008 were docked into the binding pocket generated according to arginine ligand of the crystal structure.…”

“…Molecular docking : Surflex‐Dock GeomX module in SYBYL‐X 2.0 was used to investigate the interaction between p62‐zz domain and 4 d , XIE62‐1004 and XIE2008. In brief, after the binding pocket of p62‐zz domain (PDB ID: 6MJ7) was generated based on its arginine ligand, compound 4 d , XIE62‐1004 or XIE2008 was docked into this pocket separately. The 3D visualizations of the p62‐zz‐ 4 d complex, p62‐zz‐XIE62‐1004 and p62‐zz‐XIE2008 complexes interaction were performed using PyMOL programs…”

Mechanistic Study of Triazole Based Aminodiol Derivatives in Leukemic Cells—Crosstalk between Mitochondrial Stress-Involved Apoptosis and Autophagy

“…LC3, which acts in substrate selection and autophagosome biogenesis in autophagy, is a widely recognized autophagosome marker. P62 is a protein adaptor in the autophagic proteolytic processes in regulating the sequestration of toxic, aggregate-prone cargo proteins [28,29]. The autophagy in this study was examined using the immunofluorescence detection of LC3.…”