Ca2+/calmodulin-dependent protein kinase II β decodes ER Ca2+ transients to trigger autophagosome formation

Qiaoxia Zheng; Huan Zhang; Hongyu Zhao; Yong Chen; Hongzhining Yang; Tingting Li; Qixu Cai; Yingyu Chen; Youjun Wang; Mingjie Zhang; Hong Zhang

doi:10.1016/j.molcel.2024.12.005

Ca²⁺/calmodulin-dependent protein kinase II β decodes ER Ca²⁺ transients to trigger autophagosome formation

Mol Cell. 2024 Dec 26:S1097-2765(24)01000-1. doi: 10.1016/j.molcel.2024.12.005. Online ahead of print.

Authors

Qiaoxia Zheng¹, Huan Zhang², Hongyu Zhao³, Yong Chen³, Hongzhining Yang⁴, Tingting Li⁴, Qixu Cai⁵, Yingyu Chen⁶, Youjun Wang⁷, Mingjie Zhang⁸, Hong Zhang⁹

Affiliations

¹ National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
² National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
³ National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁴ Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
⁵ School of Public Health, Xiamen University, Xiamen 361102, China.
⁶ Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
⁷ College of Life Sciences, Beijing Normal University, Beijing 100875, China.
⁸ School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
⁹ National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].

PMID: 39742665
DOI: 10.1016/j.molcel.2024.12.005

Abstract

In multicellular organisms, very little is known about how Ca²⁺ transients on the ER outer surface elicited by autophagy stimuli are sustained and decoded to trigger autophagosome formation. Here, we show that Ca²⁺/calmodulin-dependent protein kinase II β (CaMKIIβ) integrates ER Ca²⁺ transients to trigger liquid-liquid phase separation (LLPS) of the autophagosome-initiating FIP200 complex. In response to ER Ca²⁺ transients, CaMKIIβ is recruited from actin filaments and forms condensates, which serve as sites for the emergence of or interaction with FIP200 puncta. CaMKIIβ phosphorylates FIP200 at Thr269, Thr1127, and Ser1484 to modulate LLPS and properties of the FIP200 complex, thereby controlling its function in autophagosome formation. CaMKIIβ also controls the amplitude, duration, and propagation of ER Ca²⁺ transients during autophagy induction. CaMKIIβ mutations identified in the neurodevelopmental disorder MRD54 affect the function of CaMKIIβ in autophagy. Our study reveals that CaMKIIβ is essential for sustaining and decoding ER Ca²⁺ transients to specify autophagosome formation in mammalian cells.

Keywords: Ca(2+) transient; CaMKIIβ; FIP200; autophagosome; liquid-liquid phase separation.