On December 2nd, Dr. ZHANG Hong's lab published a research article entitled "The ER-localized transmembrane protein TMEM39A/SUSR2 regulates autophagy by controlling the trafficking of the PtdIns(4)P phosphatase SAC1" in Molecular Cell. This study revealed that the ER-localized transmembrane protein TMEM39A/SUSR2 acts as an adaptor to promote the ER exit of the PtdIn(4)P phosphatase SAC1. Depletion of SUSR2 increases the levels of late endosomal/lysosomal PtdIn(4)P, facilitating the recruitment of the HOPS complex for autophagosome maturation.

Autophagy involves the enclosure of cytoplasmic material in the autophagosome and its subsequent delivery to the lysosome for degradation. Dr. ZHANG Hong's lab established C. elegans as one of the premier genetic models to study autophagy. Using this model, Hong's lab carried out the first systematic genetic screens in multicellular organisms and identified a set of metazoan-specific autophagy genes, known as epg genes. His lab is also investigating how autophagy activity is regulated during C. elegans development. In this study, they identified that inactivation of D1007.5, named as susr-2 (suppressor of SQST-1 aggregates in rpl-43 mutants), promotes autophagic degradation of SQST-1 aggregates. The mammalian SUSR-2 homolog TMEM39A, which is an ER-localized transmembrane protein, is a susceptibility locus for multiple autoimmune diseases. However, the molecular function of TMEM39A remains completely unknown.

In this study, the authors showed that the ER-localized transmembrane protein TMEM39A/SUSR2 modulates autophagy activity by regulating the distribution and levels of PtdIns(4)P. In SUSR2 KD cells, PtdIns(4)P levels on late endosomes/lysosomes are elevated, promoting recruitment of the HOPS complex to facilitate autophagosome maturation. SUSR2 interacts with SAC1 and the COPII coat proteins SEC23/SEC24, acting as an adaptor to facilitate the ER-to-Golgi transport of SAC1. Accumulation of SAC1 on the ER in SUSR2 KD cells also enhances targeting of the autophagy initiation complex for autophagosome formation. This study reveals an essential role of SUSR2 in controlling the spatial distribution and levels of intracellular PtdIns(4)P pools, and provides insights into the pathogenesis of diseases linked with TMEM39A/SUSR2 mutations.

Figure. SUSR2 regulates autophagy by controlling the trafficking of the PtdIns(4)P phosphatase SAC1.
（Image by Dr. ZHANG Hong's group)

Dr. ZHANG Hong from the Institute of Biophysics is the corresponding author. Dr. MIAO Guangyan and Dr. ZHANG Yujie from Dr. ZHANG Hong's lab are the co-first authors of this paper. Dr. CHEN Di from Dr. ZHANG Hong's lab also contributed to this work. This work was supported by the Beijing Municipal Science and Technology Committee, National Natural Science Foundation of China, Chinese Ministry of Science and Technology, Strategic Priority Research Program of the Chinese Academy of Sciences (CAS), and Key Research Program of Frontier Sciences, CAS.

Contact: ZHANG Hong
Institute of Biophysics, Chinese Academy of Sciences
Beijing 100101, China
Phone: 86-10-64848238
Email: hongzhang@ibp.ac.cn

(Reported by Dr. ZHANG Hong's group)