Journal
EMBO JOURNAL
Volume 36, Issue 18, Pages 2790-2807Publisher
WILEY
DOI: 10.15252/embj.201796463
Keywords
autophagy; NDP52; Rab35; TBK1
Categories
Funding
- Research Program on Emerging and Reemerging Infectious Diseases [17824541]
- J-PRIDE from the Japan Agency for Medical Research and Development, AMED [17fm0208030h0001]
- Daiichi Sankyo Foundation of Life Science
- [25293370]
- [15K15130]
- [26462776]
- [16H05188]
- [17K19552]
- [14J05847]
- Grants-in-Aid for Scientific Research [16H05188] Funding Source: KAKEN
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Autophagy targets intracellular molecules, damaged organelles, and invading pathogens for degradation in lysosomes. Recent studies have identified autophagy receptors that facilitate this process by binding to ubiquitinated targets, including NDP52. Here, we demonstrate that the small guanosine triphosphatase Rab35 directs NDP52 to the corresponding targets of multiple forms of autophagy. The active GTP-bound form of Rab35 accumulates on bacteria-containing endosomes, and Rab35 directly binds and recruits NDP52 to internalized bacteria. Additionally, Rab35 promotes interaction of NDP52 with ubiquitin. This process is inhibited by TBC1D10A, a GAP that inactivates Rab35, but stimulated by autophagic activation via TBK1 kinase, which associates with NDP52. Rab35, TBC1D10A, and TBK1 regulate NDP52 recruitment to damaged mitochondria and to autophagosomes to promote mitophagy and maturation of autophagosomes, respectively. We propose that Rab35-GTP is a critical regulator of autophagy through recruiting autophagy receptor NDP52.
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