Jo, D.S., Park, S.J., Kim, A.K., Park, N.Y., Kim, J.B., Bae, J.E., Park, H.J., Shin, J.H., Chang, J.W., Kim, P.K., Jung, Y.K., Koh, J.Y., Choe, S.K., Lee, K.S., Cho, D.H. (2020). Loss of HSPA9 induces peroxisomal degradation by increasing pexophagy.  Autophagy 16(11): 1989--2003.

FBrf0247089

Research paper

Quality control of peroxisomes is essential for cellular homeostasis. However, the mechanism underlying pexophagy is largely unknown. In this study, we identified HSPA9 as a novel pexophagy regulator. Downregulation of HSPA9 increased macroautophagy/autophagy but decreased the number of peroxisomes in vitro and in vivo. The loss of peroxisomes by HSPA9 depletion was attenuated in SQSTM1-deficient cells. In HSPA9-deficient cells, the level of peroxisomal reactive oxygen species (ROS) increased, while inhibition of ROS blocked pexophagy in HeLa and SH-SY5Y cells. Importantly, reconstitution of HSPA9 mutants found in Parkinson disease failed to rescue the loss of peroxisomes, whereas reconstitution with wild type inhibited pexophagy in HSPA9-depleted cells. Knockdown of Hsc70-5 decreased peroxisomes in Drosophila, and the HSPA9 mutants failed to rescue the loss of peroxisomes in Hsc70-5-depleted flies. Taken together, our findings suggest that the loss of HSPA9 enhances peroxisomal degradation by pexophagy.

PMC7595578 (PMC) (EuropePMC)