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Surf4, cargo trafficking, lipid metabolism, and therapeutic implications
Yishi Shen1 , Hong-Mei Gu1 , Shucun Qin2,* , Da-Wei Zhang1,*
1Group on the Molecular and Cell Biology of Lipids and Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6R 2G3, Canada
2Institute of Atherosclerosis in Shandong First Medical University (Shandong Academy of Medical Sciences), Taian 271016, China
*Correspondence to:Shucun Qin , Da-Wei Zhang ,
J Mol Cell Biol, Volume 14, Issue 9, September 2022, mjac063,
Keyword: VLDL secretion, cargo receptor, PCSK9, lipid metabolism, atherosclerosis, trafficking

Surfeit 4 is a polytopic transmembrane protein that primarily resides in the endoplasmic reticulum (ER) membrane. It is ubiquitously expressed and functions as a cargo receptor, mediating cargo transport from the ER to the Golgi apparatus via the canonical coat protein complex II (COPII)-coated vesicles or specific vesicles. It also participates in ER–Golgi protein trafficking through a tubular network. Meanwhile, it facilitates retrograde transportation of cargos from the Golgi apparatus to the ER through COPI-coated vesicles. Surf4 can selectively mediate export of diverse cargos, such as PCSK9 very low-density lipoprotein (VLDL), progranulin, α1-antitrypsin, STING, proinsulin, and erythropoietin. It has been implicated in facilitating VLDL secretion, promoting cell proliferation and migration, and increasing replication of positive-strand RNA viruses. Therefore, Surf4 plays a crucial role in various physiological and pathophysiological processes and emerges as a promising therapeutic target. However, the molecular mechanisms by which Surf4 selectively sorts diverse cargos for ER–Golgi protein trafficking remain elusive. Here, we summarize the most recent advances in Surf4, focusing on its role in lipid metabolism.