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Dev. Cell, February 06, 2025 | https://doi.org/10.1016/j.devcel.2025.01.011 Tubular ER structures shaped by ER-phagy receptors engage in stress-induced Golgi bypass

Min Seok Song,^1,2,8 Hun Ju Sim,^1,8 Sung Ho Eun,^1,3,8 Min Kyo Jung,^4,8 Su Jin Hwang,^5,8 Min Hee Ham,⁵ Kihyuck Kwak,⁵ Hea Ji Lee,⁶ Jin Young Kim,^6,7 Dong Geon Jang,¹ Hee Chun Chung,⁵ Dong Hoon Shin,¹ Ye Jin Kim,¹ Shin Hye Noh,¹ Ji Young Mun,⁴ Jae Myun Lee,^5,*and Min Goo Lee ^1,9,*

¹Department of Pharmacology, Woo Choo Lee Institute for Precision Drug Development, Graduate School of Medical Science Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
²Department of Physiology, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea
³Department of Gastroenterology, National Health Insurance Service Ilsan Hospital, Goyang 10444, Republic of Korea
⁴Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41068, Republic of Korea
⁵Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Graduate School of Medical Science Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
⁶Digital Omics Research Center, Korea Basic Science Institute (KBSI), Ochang, Cheongju 28119, Republic of Korea
⁷Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
⁸These authors contributed equally
⁹Lead contact

^*Corresponding authors: correspondence to Jae Myun Lee or Min Goo Lee

Abstract

Cellular stresses, particularly endoplasmic reticulum (ER) stress induced by ER-to-Golgi transport blockade, trigger Golgi-independent secretion of cytosolic and transmembrane proteins. However, the molecular mechanisms underlying this unconventional protein secretion (UPS) remain largely elusive. Here, we report that an ER tubulovesicular structure (ER tubular body [ER-TB]), shaped by the tubular ER-phagy receptors ATL3 and RTN3L, plays an important role in stress-induced UPS of transmembrane proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Correlative light-electron microscopy analyses demonstrate the formation of ER-TB under UPS-inducing conditions in HEK293 and HeLa cells. Individual gene knockdowns of ATL3 and RTN3 inhibit ER-TB formation and the UPS of trafficking-deficient ΔF508-CFTR. Combined supplementation of ATL3 and RTN3L induces ER-TB formation and UPS. ATL3 also participates in the SARS-CoV-2-associated convoluted membrane formation and Golgi-independent trafficking of SARS-CoV-2 spike protein. These findings suggest that ER-TB serves a common function in mediating stress-induced UPS, which participates in various physiological and pathophysiological processes.

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형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-07)
연구진국내 연구진
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