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Nat. Commun., 06 April 2026 | https://doi.org/10.1038/s41467-026-71409-9 VPS26A retromer complex and SNX27 mediate stress-induced Golgi bypass of membrane proteins

Ye Jin Kim^1,†, Chaeyoung Lee^1,†, Soo Kyung Seo¹, Jae Won Roh¹, Hye Ryung Lee¹, Su Jin Hwang², Nienping Chang³, Hee Seong Choi³, Dong Hoon Shin¹, Hui Kwon Kim⁴, Han Sang Kim⁵, Hyun-Soo Cho³, Jae Myun Lee², Heon Yung Gee¹, Min Goo Lee^1,6* and Shin Hye Noh^1,6*

¹Department of Pharmacology, Brain Korea 21 Project for Medical Science, Woo Choo Lee Institute for Precision Drug Development, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
²Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
³Department of Systems Biology and Division of Life Sciences, Yonsei University, Seoul 03722, Republic of Korea.
⁴Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea.
⁵Division of Medical Oncology, Departments of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
⁶Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

^†These authors contributed equally to this work.
^*Corresponding authors: Min Goo Lee and Shin Hye Noh

Abstract

Many proteins can reach the cell surface through a Golgi-independent unconventional protein secretion (UPS) pathway, particularly under cellular stress conditions. However, the molecular mechanisms that mediate UPS remain largely elusive. In this study, VPS26A-containing retromer complex, along with the sorting nexin SNX27, is identified as a regulator of UPS of transmembrane proteins, including the trafficking-deficient ∆F508 mutant CFTR, which causes cystic fibrosis, and the SARS-CoV-2 spike protein, associated with COVID-19. A targeted CRISPR knockout screen identified VPS26A as a key contributor in the UPS of ∆F508-CFTR. Subsequent molecular analyses revealed that SNX27 recruits ∆F508-CFTR to the VPS26A-VPS35-VPS29 retromer complex, facilitating its transport to the cell surface under UPS-inducing conditions. Additionally, VPS26A and SNX27 are necessary for UPS of the spike protein, enabling the formation of intact SARS-CoV-2 virions. These findings suggest that the retromer complex and SNX27, known for their roles in recycling endosomes, mediate previously unrecognized functions in the UPS of transmembrane proteins.

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