The function of ER-phagy receptors is regulated through phosphorylation-dependent ubiquitination pathways

Rayene Berkane, Hung Ho-Xuan, Marius Glogger, Pablo Sanz-Martinez, Lorène Brunello, Tristan Glaesner, Santosh Kumar Kuncha, Katharina Holzhüter, Sara Cano-Franco, Viviana Buonomo, Paloma Cabrerizo-Poveda, Ashwin Balakrishnan, Georg Tascher, Koraljka Husnjak, Thomas Juretschke, Mohit Misra, Alexis González, Volker Dötsch, Paolo Grumati, Mike Heilemann and Alexandra Stolz ()
Additional contact information
Rayene Berkane: Goethe University
Hung Ho-Xuan: Goethe University
Marius Glogger: Goethe University
Pablo Sanz-Martinez: Goethe University
Lorène Brunello: Goethe University
Tristan Glaesner: Goethe University
Santosh Kumar Kuncha: Goethe University
Katharina Holzhüter: Goethe University
Sara Cano-Franco: Goethe University
Viviana Buonomo: Telethon Institute of Genetics and Medicine (TIGEM)
Paloma Cabrerizo-Poveda: Goethe University
Ashwin Balakrishnan: Goethe University
Georg Tascher: Goethe University
Koraljka Husnjak: Goethe University
Thomas Juretschke: Institute of Molecular Biology
Mohit Misra: Goethe University
Alexis González: Goethe University
Volker Dötsch: Goethe University
Paolo Grumati: Telethon Institute of Genetics and Medicine (TIGEM)
Mike Heilemann: Goethe University
Alexandra Stolz: Goethe University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Selective autophagy of the endoplasmic reticulum (ER), known as ER-phagy, is an important regulator of ER remodeling and essential to maintain cellular homeostasis during environmental changes. We recently showed that members of the FAM134 family play a critical role during stress-induced ER-phagy. However, the mechanisms on how they are activated remain largely unknown. In this study, we analyze phosphorylation of FAM134 as a trigger of FAM134-driven ER-phagy upon mTOR (mechanistic target of rapamycin) inhibition. An unbiased screen of kinase inhibitors reveals CK2 to be essential for FAM134B- and FAM134C-driven ER-phagy after mTOR inhibition. Furthermore, we provide evidence that ER-phagy receptors are regulated by ubiquitination events and that treatment with E1 inhibitor suppresses Torin1-induced ER-phagy flux. Using super-resolution microscopy, we show that CK2 activity is essential for the formation of high-density FAM134B and FAM134C clusters. In addition, dense clustering of FAM134B and FAM134C requires phosphorylation-dependent ubiquitination of FAM134B and FAM134C. Treatment with the CK2 inhibitor SGC-CK2-1 or mutation of FAM134B and FAM134C phosphosites prevents ubiquitination of FAM134 proteins, formation of high-density clusters, as well as Torin1-induced ER-phagy flux. Therefore, we propose that CK2-dependent phosphorylation of ER-phagy receptors precedes ubiquitin-dependent activation of ER-phagy flux.

Date: 2023
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DOI: 10.1038/s41467-023-44101-5

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