Snx4-assisted vacuolar targeting of transcription factors defines a new autophagy pathway for controlling <i>ATG</i> expression

Autophagy, in part, is controlled by the repression and activation of autophagy-related (<i>ATG</i>) genes. Here, we describe a new selective autophagy pathway that targets functional transcriptional regulators to control their activity. This pathway is activated in response to nitrogen starvation and recycles transcriptional activators (Msn2 and Rim15) and a repressor (Ssn2/Med13) of <i>ATG</i> expression. Further analysis of Ssn2/Med13 vacuolar proteolysis revealed that this pathway utilizes the core autophagic machinery. However, it is independent of known nucleophagy mechanisms, receptor proteins, and the scaffold protein Atg11. Instead, Ssn2/Med13 exits the nucleus through the nuclear pore complex (NPC) and associates with the cytoplasmic nucleoporin Gle1, a member of the RNA remodeling complex. Dbp5 and Nup159, that act in concert with Gle1, are also required for Ssn2/Med13 clearance. Ssn2/Med13 is retrieved from the nuclear periphery and degraded by Atg17-initiated phagophores anchored to the vacuole. Efficient transfer to phagophores depends on the sorting nexin heterodimer Snx4/Atg24-Atg20, which binds to Atg17, and relocates to the perinucleus following nitrogen starvation. To conclude, this pathway defines a previously undescribed autophagy mechanism that targets select transcriptional regulators for rapid vacuolar proteolysis, utilizing the RNA remodeling complex, the sorting nexin heterodimer Snx4-Atg20, Atg17, and the core autophagic machinery. It is physiologically relevant as this Snx4-assisted vacuolar targeting pathway permits cells to fine-tune the autophagic response by controlling the turnover of both positive and negative regulators of <i>ATG</i> transcription. <b>Abbreviations:</b> AIM: Atg8 interacting motif; ATG: autophagy-related; CKM: CDK8 kinase module; IDR: intrinsically disordered region; IP₆: phosphoinositide inositol hexaphosphate; NPC: nuclear pore complex; PAS: phagophore assembly site; UPS: ubiquitin-proteasomal system细胞自噬（Autophagy）的调控部分依赖于自噬相关（autophagy-related, ATG）基因的抑制与激活。本文报道了一条全新的选择性自噬通路，该通路靶向功能性转录调控因子以调控其活性。该通路响应氮饥饿而被激活，并降解ATG基因表达的转录激活因子（Msn2与Rim15）以及转录阻遏因子（Ssn2/Med13）。 对Ssn2/Med13的液泡蛋白水解过程的进一步分析显示，该通路依赖核心自噬机器，但不依赖已知的核自噬机制、受体蛋白以及支架蛋白Atg11。取而代之的是，Ssn2/Med13通过核孔复合体（nuclear pore complex, NPC）从细胞核内转出，并与细胞质侧的核孔蛋白Gle1结合——Gle1属于RNA重塑复合体成员。与Gle1协同作用的Dbp5与Nup159，同样参与Ssn2/Med13的清除过程。Ssn2/Med13从核周区域被招募，并被锚定在液泡上、由Atg17起始的吞噬泡降解。 高效招募至吞噬泡的过程依赖分选连接蛋白异二聚体Snx4/Atg24-Atg20，该复合物可结合Atg17，并在氮饥饿后重新定位至核周区域。 综上，本研究定义了一种此前未被报道的自噬机制：该通路靶向特定转录调控因子进行快速液泡蛋白水解，其过程依赖RNA重塑复合体、分选连接蛋白异二聚体Snx4-Atg20、Atg17以及核心自噬机器。该通路具有生理相关性：借助Snx4辅助的液泡靶向通路，细胞可通过调控ATG转录的正负调控因子的周转，精准调节自噬应答。 <b>缩写说明：</b>AIM：Atg8互作基序；ATG：自噬相关；CKM：CDK8激酶模块；IDR：内在无序区域；IP₆：肌醇六磷酸；NPC：核孔复合体；PAS：吞噬泡组装位点；UPS：泛素-蛋白酶体系统

搜集汇总

背景与挑战

背景概述

该数据集描述了一项研究，发现了一种新的选择性自噬途径，该途径在氮饥饿条件下激活，通过Snx4辅助的空泡靶向机制靶向转录调节因子（如Msn2和Ssn2/Med13），以控制自噬相关基因（ATG）的表达。该途径利用核心自噬机制但独立于已知核自噬，涉及RNA重塑复合物和分选连接蛋白Snx4-Atg20，具有生理相关性，允许细胞微调自噬反应。