Genome-wide screen identifies signaling pathways that regulate autophagy during Caenorhabditis elegans development

• Published in: EMBO reports 2014-06, Vol.15 (6), p.705-713
• Main Authors: Guo, Bin, Huang, Xinxin, Zhang, Peipei, Qi, Linxiang, Liang, Qianqian, Zhang, Xuebo, Huang, Jie, Fang, Bin, Hou, Wenru, Han, Jinghua, Zhang, Hong
• Format: Article
• Language: English
• Subjects: Aggregates; Animals; Autophagy; Autophagy - physiology; Basic Helix-Loop-Helix Transcription Factors - metabolism; Caenorhabditis elegans; Caenorhabditis elegans - growth & development; Caenorhabditis elegans Proteins - drug effects; Caenorhabditis elegans Proteins - metabolism; Carrier Proteins - metabolism; EMBO07; EMBO20; EMBO37; Endoplasmic Reticulum Stress - physiology; ER stress; Fluorescent Antibody Technique; Gene expression; Gene Expression Regulation - genetics; Genomes; Inactivation; Intestinal Mucosa - metabolism; mitochondrial stress; Morphogenesis - physiology; Nematodes; Proteasome Endopeptidase Complex - metabolism; Ribosomal Proteins - drug effects; Ribosomal Proteins - metabolism; RNA Interference; Scientific Report; Scientific Reports; Signal Transduction - physiology; Stress response; Transcription Factors - metabolism
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1002/embr.201338310

The mechanisms that coordinate the regulation of autophagy with developmental signaling during multicellular organism development remain largely unknown. Here, we show that impaired function of ribosomal protein RPL‐43 causes an accumulation of SQST‐1 aggregates in the larval intestine, which are removed upon autophagy induction. Using this model to screen for autophagy regulators, we identify 139 genes that promote autophagy activity upon inactivation. Various signaling pathways, including Sma/Mab TGF‐β signaling, lin‐35 /Rb signaling, the XBP‐1‐mediated ER stress response, and the ATFS‐1‐mediated mitochondrial stress response, regulate the expression of autophagy genes independently of the TFEB homolog HLH‐30. Our study thus provides a framework for understanding the role of signaling pathways in regulating autophagy under physiological conditions. Synopsis A genome‐wide screen for regulators of autophagy activity during Caenorhabditis elegans development identifies various signaling pathways that inhibit autophagy activity. Inactivation of some of these pathways increases autophagy gene expression independently of TFEB. SQST‐1 aggregates in rpl‐43 mutants are degraded by elevated autophagy activity. Inactivation of Sma/Mab TGF‐β signaling activates autophagy activity by transcriptional upregulation of autophagy genes. The bZip transcription factor ATFS‐1 mediates mitochondrial stress‐induced autophagy. Impairment of proteasome function elevates autophagy activity via XBP‐1‐mediated ER stress response. Graphical Abstract A screen for regulators of autophagy during C. elegans development identifies 139 genes and multiple pathways that inhibit autophagy. Interestingly, some pathways regulate the transcription of autophagy genes in a TFEB‐independent manner.