Achievements in 2025

1) We identified RAB8A, a small RAB GTPase that controls vesicular trafficking, as an interacting factor with optineurin (OPTN), a known autophagy adaptor. We determined the crystal structure of the OPTN–RAB8A complex at 1.83 Å resolution and elucidated the specific interaction mechanism between these proteins. This work revealed the functional role of OPTN in regulating both vesicular trafficking and selective autophagy (Okatsu et al. 2025 Genes Cells).

2) Our previously identified autophagy regulator, the BCAS3-PHAF1 complex, was recently reported to be the causative factor for the neurodevelopmental disorder HEMARS. Investigating the link between autophagy and this neurological disorder, we found that disease-associated BCAS3 mutations impeded the interactions with PHAF1, which impaired autophagy activity. Moreover, the loss of BCAS3 and PHAF1 in Drosophila melanogaster leads to the accumulation of autophagic cargo in vivo, impaired tissue remodeling, and a shortened lifespan. Our findings, therefore, provide new insights into the pathogenesis of HEMARS by highlighting, at both the molecular and organismal levels, the critical roles of BCAS3 and PHAF1 in autophagy regulation (Kojima et al. 2025 submitted).

Publications

Papers I 2025

• Okatsu K, et al. Functional and Structural Insights Into Complex Formation Between OPTN Leucine Zipper Domain and RAB8A. Genes Cells. 2025 Sep;30(5):e70043. doi: 10.1111/gtc.70043.
• Endo A, et al. Ubiquitination-activated TAB-TAK1-IKK-NF-κB axis modulates gene expression for cell survival in the lysosomal damage response. Elife. 2025 Sep 24;14:RP106901. doi: 10.7554/eLife.106901.
• Watanabe A, et al. The reaction mechanism for glycolysis side product degradation by Parkinson's disease-linked DJ-1. J Cell Biol. 2025 Aug 4;224(8):e202411078. doi: 10.1083/jcb.202411078. Epub 2025 Jun 4.

Key papers

• Hsu MC, et al. Mitochondrial YME1L1 governs unoccupied protein translocase channels. Nat Cell Biol. 2025 Feb;27(2):309-321. doi: 10.1038/s41556-024-01571-z. Epub 2025 Jan 7.
• Endo R, et al. TBK1 adaptor AZI2/NAP1 regulates NDP52-driven mitochondrial autophagy. J Biol Chem. 2024 Oct;300(10):107775. doi: 10.1016/j.jbc.2024.107775. Epub 2024 Sep 12.
• Yamano K, et al. Optineurin provides a mitophagy contact site for TBK1 activation. EMBO J. 2024 Mar;43(5):754-779. doi: 10.1038/s44318-024-00036-1. Epub 2024 Jan 29.
• Hayashida R, et al. Elucidation of ubiquitin-conjugating enzymes that interact with RBR-type ubiquitin ligases using a liquid-liquid phase separation-based method. J Biol Chem. 2023 Feb;299(2):102822. doi: 10.1016/j.jbc.2022.102822. Epub 2022 Dec 21.
• Kojima W, et al. Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy. Autophagy. 2021 Aug;17(8):2011-2036. doi: 10.1080/15548627.2021.1874133. Epub 2021 Jan 26.
• Yamano K, et al. Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy. J Cell Biol. 2020 Sep 7;219(9):e201912144. doi: 10.1083/jcb.201912144.