Snx4-mediated nucleophagy targets transcription factors controllingATGgene expression

ABSTRACT Autophagy is controlled in part by the repression and activation of Autophagy-related ( ATG ) gene transcription. Here, we demonstrate that the conserved Cdk8 Kinase Module (CKM) of the mediator complex represses transcription of several ATG genes. To relieve this repression following nitrogen starvation, Med13 is rapidly degraded via a novel selective autophagy mechanism. This pathway requires the core autophagy machinery but is independent of known nucleophagy systems. It requires the cytosolic filament nucleoporin Gle1, the sorting nexin Snx4-Atg20 heterodimer, and the scaffold protein Atg17. This suggests a model where Med13 traverses through the nuclear pore complex, passing from Gle1 to Snx4. Snx4 then transports Med13 to autophagosomes by binding to Atg17. This previously unidentified nucleophagy pathway also mediates the autophagic degradation of two transcriptional activators of ATG genes (Rim15, Msn2) suggesting that this mechanism targets transcription factors that regulate ATG expression. This system provides a new level of selectivity, permitting the cell to fine-tune the autophagic response by controlling the turnover of both positive and negative ATG transcription factors.