UBR4/POE facilitates secretory trafficking to maintain circadian clock synchrony

Sara Hegazi, Arthur H. Cheng, Joshua J. Krupp, Takafumi Tasaki, Jiashu Liu, Daniel A. Szulc, Harrod H. Ling, Julian Rios Garcia, Shavanie Seecharran, Tayebeh Basiri, Mehdi Amiri, Zobia Anwar, Safa Ahmad, Kamar Nayal, Nahum Sonenberg, Bao-Hua Liu, Hai-Ling Margaret Cheng, Joel D. Levine () and Hai-Ying Mary Cheng ()
Additional contact information
Sara Hegazi: University of Toronto Mississauga
Arthur H. Cheng: University of Toronto Mississauga
Joshua J. Krupp: University of Toronto Mississauga
Takafumi Tasaki: Medical Research Institute, Kanazawa Medical University
Jiashu Liu: University of Toronto Mississauga
Daniel A. Szulc: University of Toronto
Harrod H. Ling: University of Toronto Mississauga
Julian Rios Garcia: University of Toronto Mississauga
Shavanie Seecharran: University of Toronto Mississauga
Tayebeh Basiri: Goodman Cancer Research Center, McGill University
Mehdi Amiri: Goodman Cancer Research Center, McGill University
Zobia Anwar: University of Toronto Mississauga
Safa Ahmad: University of Toronto Mississauga
Kamar Nayal: University of Toronto Mississauga
Nahum Sonenberg: Goodman Cancer Research Center, McGill University
Bao-Hua Liu: University of Toronto Mississauga
Hai-Ling Margaret Cheng: University of Toronto
Joel D. Levine: University of Toronto Mississauga
Hai-Ying Mary Cheng: University of Toronto Mississauga

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Ubiquitin ligases control the degradation of core clock proteins to govern the speed and resetting properties of the circadian pacemaker. However, few studies have addressed their potential to regulate other cellular events within clock neurons beyond clock protein turnover. Here, we report that the ubiquitin ligase, UBR4/POE, strengthens the central pacemaker by facilitating neuropeptide trafficking in clock neurons and promoting network synchrony. Ubr4-deficient mice are resistant to jetlag, whereas poe knockdown flies are prone to arrhythmicity, behaviors reflective of the reduced axonal trafficking of circadian neuropeptides. At the cellular level, Ubr4 ablation impairs the export of secreted proteins from the Golgi apparatus by reducing the expression of Coronin 7, which is required for budding of Golgi-derived transport vesicles. In summary, UBR4/POE fulfills a conserved and unexpected role in the vesicular trafficking of neuropeptides, a function that has important implications for circadian clock synchrony and circuit-level signal processing.

Date: 2022
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DOI: 10.1038/s41467-022-29244-1

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