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J Cell Biol. 2019 Jan 31. pii: jcb.201712120. doi: 10.1083/jcb.201712120. [Epub ahead of print]

The AAA+ ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets.

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Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan.
Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto, Japan
Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, Sagamihara, Japan.
Laboratory of Molecular Cell Dynamics, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.
Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto, Japan.


Mysterin, also known as RNF213, is an intracellular protein that forms large toroidal oligomers. Mysterin was originally identified in genetic studies of moyamoya disease (MMD), a rare cerebrovascular disorder of unknown etiology. While mysterin is known to exert ubiquitin ligase and putative mechanical ATPase activities with a RING finger domain and two adjacent AAA+ modules, its biological role is poorly understood. Here, we report that mysterin is targeted to lipid droplets (LDs), ubiquitous organelles specialized for neutral lipid storage, and markedly increases their abundance in cells. This effect was exerted primarily through specific elimination of adipose triglyceride lipase (ATGL) from LDs. The ubiquitin ligase and ATPase activities of mysterin were both important for its proper LD targeting. Notably, MMD-related mutations in the ubiquitin ligase domain of mysterin significantly impaired its fat-stabilizing activity. Our findings identify a unique new regulator of cytoplasmic LDs and suggest a potential link between the pathogenesis of MMD and fat metabolism.


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