RESUMO
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-ß 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.
Assuntos
Autofagia/fisiologia , Proteínas de Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Regulação da Expressão Gênica/genética , Morfogênese/fisiologia , Proteínas Ribossômicas/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Transporte/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Imunofluorescência , Mucosa Intestinal/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Interferência de RNA , Proteínas Ribossômicas/metabolismoRESUMO
In response to stress conditions, autophagy activity in multicellular organisms is systemically modulated to ensure maintenance of cellular homeostasis at an organismal level. Very little is known about the intercellular signals that elicit the long-range organism-wide autophagy response. Here we showed that during Caenorhabditis elegans development, loss of cuticle annular furrow collagens elicits autophagy in the hypodermis, intestine, and muscle. The cilia of sensory neurons with cuticle-localized endings are essential for triggering this systemic response. The TGFß-like molecule DAF-7, which is secreted in part from a specific pair of ciliated neurons, acts as a systemic factor that activates a canonical TGFß signaling pathway in distant tissues to induce autophagy. We also showed that AAK-2/AMPK and the STAT-like protein STA-2 act differentially in different tissues for autophagy activation. Our study reveals a circuit that senses and transduces the signal from the damaged cuticle to activate systemic autophagy during animal development.