Phosphorylation of FAM134C by CK2 controls starvation-induced ER-phagy

Di Lorenzo, Giorgia; Iavarone, Francescopaolo; Maddaluno, Marianna; Plata-Gómez, Ana Belén; Aureli, Simone; Quezada Meza, Camila Paz; Cinque, Laura; Palma, Alessandro; Reggio, Alessio; Cirillo, Carmine; Sacco, Francesca; Stolz, Alexandra; Napolitano, Gennaro; Marin, Oriano; Pinna, Lorenzo A.; Ruzzene, Maria; Limongelli, Vittorio; Efeyan, Alejo; Grumati, Paolo; Settembre, Carmine

doi:10.1126/sciadv.abo12

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Journal article

Phosphorylation of FAM134C by CK2 controls starvation-induced ER-phagy

Di Lorenzo, Giorgia Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Iavarone, Francescopaolo Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Maddaluno, Marianna Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Plata-Gómez, Ana Belén Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Aureli, Simone ORCID Euler Institute (EUL), Università della Svizzera italiana, Switzerland
Quezada Meza, Camila Paz Department of Biomedical Sciences, University of Padova, Padova, Italy
Cinque, Laura Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Palma, Alessandro Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Reggio, Alessio Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Cirillo, Carmine Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Sacco, Francesca Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
Stolz, Alexandra Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany ; Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University, Frankfurt am Main, Germany
Napolitano, Gennaro Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Marin, Oriano Department of Biomedical Sciences, University of Padova, Padova, Italy
Pinna, Lorenzo A. Department of Biomedical Sciences, University of Padova, Padova, Italy ; CNR Neuroscience Institute, Padova, Italy
Ruzzene, Maria Department of Biomedical Sciences, University of Padova, Padova, Italy ; CNR Neuroscience Institute, Padova, Italy
Limongelli, Vittorio ORCID Euler Institute (EUL), Università della Svizzera italiana, Switzerland ; Department of Pharmacy, Federico II University, Naples, Italy
Efeyan, Alejo Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Grumati, Paolo Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy ; Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
Settembre, Carmine Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy ; Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

2022

Published in:

Science advances. - 2022, vol. 8, no. 35, p. eabo1215

English Selective degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is initiated by ER-phagy receptors, which facilitate the incorporation of ER fragments into autophagosomes. FAM134 reticulon family proteins (FAM134A, FAM134B, and FAM134C) are ER-phagy receptors with structural similarities and nonredundant functions. Whether they respond differentially to the stimulation of ER-phagy is unknown. Here, we describe an activation mechanism unique to FAM134C during starvation. In fed conditions, FAM134C is phosphorylated by casein kinase 2 (CK2) at critical residues flanking the LIR domain. Phosphorylation of these residues negatively affects binding affinity to the autophagy proteins LC3. During starvation, mTORC1 inhibition limits FAM134C phosphorylation by CK2, hence promoting receptor activation and ER-phagy. Using a novel tool to study ER-phagy in vivo and FAM134C knockout mice, we demonstrated the physiological relevance of FAM134C phosphorylation during starvation-induced ER-phagy in liver lipid metabolism. These data provide a mechanistic insight into ER-phagy regulation and an example of autophagy selectivity during starvation.

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