2. Academic Validation
  3. The interaction between E3 ubiquitin ligase Parkin and mitophagy receptor PHB2 links inner mitochondrial membrane ubiquitination to efficient mitophagy

The interaction between E3 ubiquitin ligase Parkin and mitophagy receptor PHB2 links inner mitochondrial membrane ubiquitination to efficient mitophagy

  • J Biol Chem. 2022 Nov 12;102704. doi: 10.1016/j.jbc.2022.102704.
Shan Sun 1,  Hongyu Hou 2,  Guoqiang Ma 2,  Qilian Ma 2,  Ningning Li 2,  Li Zhang 3,  Chunsheng Dong 4,  Mian Cao 5,  Kin Yip Tam 6,  Zheng Ying 7,  Hongfeng Wang 8
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
  • 2 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
  • 3 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China.
  • 4 Insititutes of Biology and Medical Science, Soochow University, Suzhou, Jiangsu 215123, China.
  • 5 Programme in Neuroscience and Behavioural Disorders, Duke-NUS Medical School, 169857, Singapore.
  • 6 Faculty of Health Sciences, University of Macau, Taipa, Macau, China. Electronic address: kintam@um.edu.mo.
  • 7 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: zheng.ying@suda.edu.cn.
  • 8 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: wanghongfeng@suda.edu.cn.
PMID: 36379251 DOI: 10.1016/j.jbc.2022.102704
Abstract

The autophagic clearance of mitochondria has been defined as Mitophagy, which is triggered by mitochondrial damage and serves as a major pathway for mitochondrial homeostasis and cellular quality control. PINK1 and Parkin-mediated Mitophagy is the most extensively studied form of Mitophagy, which has been linked to the pathogenesis of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The current paradigm of this particular Mitophagy pathway is that the ubiquitination of the outer mitochondrial membrane is the key step to enable the recognition of damaged mitochondria by the core autophagic component autophagosome. However, whether the inner mitochondrial membrane (IMM) is ubiquitinated by Parkin and its contribution to sufficient Mitophagy remain unclear. Here, using molecular, cellular, and biochemical approaches, we report that prohibitin 2 (PHB2), an essential IMM receptor for Mitophagy, is ubiquitinated by Parkin and thereby gains higher affinity to the autophagosome during Mitophagy. Our findings suggest that Parkin directly binds to PHB2 through its RING1 domain and promotes K11- and K33-linked ubiquitination on K142/K200 sites of PHB2, thereby enhancing the interaction between PHB2 and MAP1LC3B/LC3B. Interestingly and importantly, our study allows us to propose a novel model in which IMM protein PHB2 serves as both a receptor and a ubiquitin-mediated base for autophagosome recruitment to ensure efficient Mitophagy.

Keywords

MAP1LC3B/LC3B; PHB2; Parkin; mitophagy; ubiquitination.

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