Smpdl3b, short for sphingomyelin phosphodiesterase acid-like 3b, is a lipid-modifying enzyme. It is involved in regulating plasma membrane fluidity by influencing sphingolipid metabolism [3]. It also has a role in innate immunity as a negative regulator of Toll-like receptor signaling [4].

In various disease models, Smpdl3b has shown distinct functions. In diabetic kidney disease, podocyte-specific Smpdl3b deficiency in db/db mice restored kidney cortex ceramide-1-phosphate (C1P) content and protected from the disease, suggesting its role in insulin receptor signaling [3]. In radiation-induced renal injury, Smpdl3b overexpression enhanced DNA double-strand breaks (DSBs) repair in renal podocytes, while its knockdown or knockout led to a delay in DSBs repair and increased apoptosis [1]. In diabetic retinopathy, silencing Smpdl3b in db/db mice aggravated the disease by activating the NF-κB/NLRP3 pro-inflammatory pathway [2]. In acute myeloid leukemia, blocking SMPDL3B expression inhibited cell growth both in vitro and in vivo via promoting apoptosis [4]. In localized prostate cancer, SMPDL3B overexpression was observed, and its knockdown impaired PC3 cell migration [5]. In porcine reproductive and respiratory syndrome virus infection, SMPDL3B deficiency inhibited viral proliferation by modulating lipid metabolism [6].

In conclusion, Smpdl3b plays crucial roles in multiple biological processes and disease conditions, including those related to metabolism, DNA damage response, inflammation, and cancer. Gene knockout and knockdown models, especially in mice, have been instrumental in revealing its functions in diseases such as diabetic kidney disease, radiation-induced renal injury, diabetic retinopathy, acute myeloid leukemia, and prostate cancer, providing potential therapeutic targets for these diseases.

References:

1. Francis, Marina, Ahmad, Anis, Bodgi, Larry, Marples, Brian, Zeidan, Youssef H. . SMPDL3b modulates radiation-induced DNA damage response in renal podocytes. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 36, e22545. doi:10.1096/fj.202100186RR. https://pubmed.ncbi.nlm.nih.gov/36094323/

2. Zhou, Yun, Yue, Song, Li, Lihua, Chen, Lei, Chen, Jun. 2024. SMPDL3B is palmitoylated and stabilized by ZDHHC5, and its silencing aggravates diabetic retinopathy of db/db mice: Activation of NLRP3/NF-κB pathway. In Cellular signalling, 116, 111064. doi:10.1016/j.cellsig.2024.111064. https://pubmed.ncbi.nlm.nih.gov/38266744/

3. Mitrofanova, A, Mallela, S K, Ducasa, G M, Merscher, S, Fornoni, A. 2019. SMPDL3b modulates insulin receptor signaling in diabetic kidney disease. In Nature communications, 10, 2692. doi:10.1038/s41467-019-10584-4. https://pubmed.ncbi.nlm.nih.gov/31217420/

4. Qu, Huiqing, Zhu, Ye. 2021. SMPDL3B Predicts Poor Prognosis and Contributes to Development of Acute Myeloid Leukemia. In Frontiers in molecular biosciences, 8, 695601. doi:10.3389/fmolb.2021.695601. https://pubmed.ncbi.nlm.nih.gov/34504869/

5. Waldbillig, Frank, Nitschke, Katja, Abdelhadi, Abdallah, Erben, Philipp, Worst, Thomas Stefan. 2020. Phosphodiesterase SMPDL3B Gene Expression as Independent Outcome Prediction Marker in Localized Prostate Cancer. In International journal of molecular sciences, 21, . doi:10.3390/ijms21124373. https://pubmed.ncbi.nlm.nih.gov/32575490/

6. Shen, Huan-Huan, Zhao, Qin, Wen, Yi-Ping, Zeng, Lei, Yan, Qi-Gui. 2023. Porcine reproductive and respiratory syndrome virus upregulates SMPDL3B to promote viral replication by modulating lipid metabolism. In iScience, 26, 107450. doi:10.1016/j.isci.2023.107450. https://pubmed.ncbi.nlm.nih.gov/37583552/