Sdf2l1, stromal cell-derived factor 2-like 1, is an endoplasmic reticulum (ER)-localized protein. It plays a crucial role in regulating ER-associated degradation (ERAD) and ER homeostasis. Sdf2l1 is involved in pathways related to metabolism, cell proliferation, and immune-related peptide processing, and thus is of great biological importance [3,4,5]. Genetic models, such as gene knockout mouse models, have been valuable in studying its functions.

In liver-specific Sdf2l1-suppressed mice, there is insulin resistance, increased triglyceride content, and sustained ER stress, indicating its importance in glucose and lipid homeostasis [1]. In nasopharyngeal carcinoma (NPC) cells, silencing Sdf2l1 promotes cell proliferation, migration, and invasion, suggesting it may act as a tumor suppressor gene [2]. In Cohen Diabetic rats with a deletion in Sdf2l1, there is dysregulated unfolded protein response (UPR), enhanced ER stress, and impaired insulin secretion, contributing to diabetes pathophysiology [6]. In Schwann cells, Sdf2l1 down-regulation, as seen in diabetic mice, inhibits cell autophagy and neurotrophin expression by impeding the nuclear import of TFEB and CREB via KPNA3 down-regulation [7].

In summary, Sdf2l1 is essential for maintaining ER homeostasis and normal cellular functions. Its dysregulation is associated with various diseases, including obesity-related diabetes, non-alcoholic steatohepatitis, NPC, and diabetic peripheral neuropathy. Studies using gene knockout models in mice and rats have significantly contributed to understanding its role in these disease conditions.

References:

1. Sasako, Takayoshi, Ohsugi, Mitsuru, Kubota, Naoto, Kadowaki, Takashi, Ueki, Kohjiro. 2019. Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism. In Nature communications, 10, 947. doi:10.1038/s41467-019-08591-6. https://pubmed.ncbi.nlm.nih.gov/30814508/

2. Zhang, Liqian, Zhang, Zunni, Qin, Liuqun, Su, Qisheng, Mo, Wuning. 2020. SDF2L1 Inhibits Cell Proliferation, Migration, and Invasion in Nasopharyngeal Carcinoma. In BioMed research international, 2020, 1970936. doi:10.1155/2020/1970936. https://pubmed.ncbi.nlm.nih.gov/33134371/

3. Tiwari, Akansha, Schuiki, Irmgard, Zhang, Liling, Wheeler, Michael B, Volchuk, Allen. 2013. SDF2L1 interacts with the ER-associated degradation machinery and retards the degradation of mutant proinsulin in pancreatic β-cells. In Journal of cell science, 126, 1962-8. doi:10.1242/jcs.117374. https://pubmed.ncbi.nlm.nih.gov/23444373/

4. Hanafusa, Ken, Wada, Ikuo, Hosokawa, Nobuko. 2019. SDF2-like protein 1 (SDF2L1) regulates the endoplasmic reticulum localization and chaperone activity of ERdj3 protein. In The Journal of biological chemistry, 294, 19335-19348. doi:10.1074/jbc.RA119.009603. https://pubmed.ncbi.nlm.nih.gov/31624144/

5. Tongaonkar, Prasad, Selsted, Michael E. 2008. SDF2L1, a component of the endoplasmic reticulum chaperone complex, differentially interacts with {alpha}-, {beta}-, and {theta}-defensin propeptides. In The Journal of biological chemistry, 284, 5602-9. doi:10.1074/jbc.M806664200. https://pubmed.ncbi.nlm.nih.gov/19109254/

6. Yagil, Chana, Varadi-Levi, Ronen, Ifrach, Chen, Yagil, Yoram. 2023. Dysregulated UPR and ER Stress Related to a Mutation in the Sdf2l1 Gene Are Involved in the Pathophysiology of Diet-Induced Diabetes in the Cohen Diabetic Rat. In International journal of molecular sciences, 24, . doi:10.3390/ijms24021355. https://pubmed.ncbi.nlm.nih.gov/36674879/

7. Jin, Tingting, Li, Fan, Wei, Wandi, Zhu, Lin, Hao, Jun. 2025. SDF2L1 downregulation mediates high glucose-caused Schwann cell dysfunction by inhibiting nuclear import of TFEB and CREB via KPNA3. In Experimental neurology, 390, 115273. doi:10.1016/j.expneurol.2025.115273. https://pubmed.ncbi.nlm.nih.gov/40294738/