MARCH7-mediated ubiquitination decreases the solubility of ATG14 to inhibit autophagy
Xue Shi,
Wenfeng Wu,
Zhenhuan Feng,
Peiyang Fan,
Ruona Shi,
Xiaofei Zhang
Affiliations
Xue Shi
CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China
Wenfeng Wu
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510530, China
Zhenhuan Feng
CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China
Peiyang Fan
SanQuan College, Xinxiang Medical University, Xinxiang, Henan 453003, China
Ruona Shi
CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
Xiaofei Zhang
CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510530, China; Corresponding author
Summary: Autophagy is a fundamental biological process critical to all eukaryotic cellular life. Although autophagy has been increasingly studied, how its process is precisely coordinated remains an open question. ATG14 (ATG14L/Barkor) is known to play a crucial role in both autophagosome formation and autophagosome-lysosome fusion. However, how ATG14 is regulated, especially at the post-translation level, is still not clear. Here, we report that MARCH7 (membrane-associated ring-CH-type finger 7), an E3 ubiquitin ligase, inhibits autophagy by ubiquitinating ATG14. MARCH7 significantly promotes K6-, K11-, and K63-linked mixed polyubiquitination on ATG14, triggering the aggregation of ATG14 and reducing its solubility in cells. Functionally, we find that MARCH7 depletion decreases the number of aggresome-like induced structures (ALISs). Mechanistically, we show that ubiquitinated ATG14 has fewer interactions with STX17, leading to the inhibition of autophagy flux. Collectively, our study reveals a mechanism in regulating autophagy and suggests a potential strategy for the treatment of autophagy-related diseases.
