PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5

<p>Macroautophagy is induced under various stresses to remove cytotoxic materials, including misfolded proteins and their aggregates. These protein cargoes are collected by specific autophagic receptors such as SQSTM1/p62 (sequestosome 1) and delivered to phagophores for lysosomal degradation. To date, little is known about how cells sense and react to diverse stresses by inducing the activity of SQSTM1. Here, we show that the peroxiredoxin-like redox sensor PARK7/DJ-1 modulates the activity of SQSTM1 and the targeting of ubiquitin (Ub)-conjugated proteins to macroautophagy under oxidative stress caused by TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10). In this mechanism, TNFSF10 induces the N-terminal arginylation (Nt-arginylation) of the endoplasmic reticulum (ER)-residing molecular chaperone HSPA5/BiP/GRP78, leading to cytosolic accumulation of Nt-arginylated HSPA5 (R-HSPA5). In parallel, TNFSF10 induces the oxidation of PARK7. Oxidized PARK7 acts as a co-chaperone-like protein that binds the ER-derived chaperone R-HSPA5, a member of the HSPA/HSP70 family. By forming a complex with PARK7 (and possibly misfolded protein cargoes), R-HSPA5 binds SQSTM1 through its Nt-Arg, facilitating self-polymerization of SQSTM1 and the targeting of SQSTM1-cargo complexes to phagophores. The 3-way interaction among PARK7, R-HSPA5, and SQSTM1 is stabilized by the Nt-Arg residue of R-HSPA5. PARK7-deficient cells are impaired in the targeting of R-HSPA5 and SQSTM1 to phagophores and the removal of Ub-conjugated cargoes. Our results suggest that PARK7 functions as a co-chaperone for R-HSPA5 to modulate autophagic removal of misfolded protein cargoes generated by oxidative stress.</p

Association between CTQ Severity Ratings and MD Total Scores.

<p>Association between CTQ Severity Ratings and MD Total Scores.</p

Taxometric Analyses of Minimization and Denial Items.

<p>Top row: left panel—average MAMBAC curve for the observed data (dark line) in comparison to simulated taxonic data (light lines representing one standard deviation above and below the mean); right panel—average MAMBAC curve for the observed data (dark line) in comparison to simulated dimensional data (light lines representing one standard deviation above and below the mean). Middle row: left panel—average MAXEIG curve for the observed data (dark line) in comparison to simulated taxonic data (light lines representing one standard deviation above and below the mean); right panel—average MAXEIG curve for the observed data (dark line) in comparison to simulated dimensional data (light lines representing one standard deviation above and below the mean). Bottom row: left panel—average L-Mode curve for the observed data (dark line) in comparison to simulated taxonic data (light lines representing one standard deviation above and below the mean); right panel—average L-Mode curve for the observed data (dark line) in comparison to simulated dimensional data (light lines representing one standard deviation above and below the mean). Inverted U-shaped graphs for the MAMBAC procedure, peaked graphs for the MAXEIG procedure, and bimodal distributions of factor scores for the L-Mode procedure are all suggestive of taxonic structure.</p

CTQ and subscale means for clinical and community samples.

<p>CTQ and subscale means for clinical and community samples.</p

Percentages of Clinical and Community Samples in CTQ Severity Quartiles.

<p>X-Axis: Quartiles of childhood maltreatment based on total CTQ scores: none, low, moderate, and severe. Y-Axis: The percentage of subjects whose CTQ scores fall into that severity quartile. Within each quartile, the bar depicted on the left represents the percentage of clinical subjects (n = 5429–5876), and the bar on the right represents the percentage of community subjects (n = 12432–12915). Notably, the largest relative percentage of community subjects was in the “none” maltreatment quartile. That trend was reversed in the “moderate” and “severe” categories, where double the percentage of subjects were in the clinical group.</p

Associations between MD Subscale Scores and Community versus Clinical Criterion.

<p>Associations between MD Subscale Scores and Community versus Clinical Criterion.</p