Cavin1, also known as caveolae-associated protein 1, is essential for caveolae biogenesis, working together with caveolin 1. Caveolae are involved in multiple cellular processes such as control of membrane tension, signaling cascades, and lipid sorting [3,4,5]. Cavin1 may also be involved in various pathways related to lipid metabolism, cell-cell communication, and signal transduction. Understanding Cavin1's function can be facilitated through genetic models like gene knockout (KO) or conditional knockout (CKO) mouse models.

In the context of drug-induced QT prolongation (diLQT), Cavin1 expression in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) affects the sensitivity to hERG blockers. Higher Cavin1 expression in more sensitive iPS-CMs leads to a rapid translocation of hERG channels from the membrane to cytoskeleton-associated fractions upon sotalol application, reducing the delayed-rectifier potassium current (IKr) [1]. In glioblastoma, EPIC-1042, a small-molecular inhibitor, can interrupt the interaction between PTRF/Cavin1 and caveolin-1, reducing temozolomide (TMZ) efflux and promoting PARP1 degradation via autolysosomes [2]. In congenital generalized lipodystrophy type 4 (CGL4), a novel pathogenic mutation in the CAVIN1/PTRF gene was found in two siblings, resulting in a phenotype characterized by lack of adipose tissue, muscular dystrophy, and other symptoms [3]. Cavin1 deficiency in C57BL/6J mice causes neonatal death due to disorder of hepatic glycogen metabolism and impaired fenestration in liver sinusoidal endothelial cells (LSECs) [6].

In summary, Cavin1 plays crucial roles in caveolae biogenesis, which impacts diverse biological processes. Its study through KO/CKO mouse models has provided insights into diseases such as diLQT, glioblastoma, CGL4, and neonatal metabolic disorders related to hepatic function. These findings contribute to a better understanding of the underlying mechanisms of these diseases and may potentially lead to new therapeutic strategies.

References:

1. Al Sayed, Zeina R, Pereira, Céline, Le Borgne, Rémi, Trégouët, David-Alexandre, Hulot, Jean-Sébastien. 2024. CAVIN1-Mediated hERG Dynamics: A Novel Mechanism Underlying the Interindividual Variability in Drug-Induced Long QT. In Circulation, 150, 563-576. doi:10.1161/CIRCULATIONAHA.123.063917. https://pubmed.ncbi.nlm.nih.gov/38682330/

2. Hong, Biao, Yang, Eryan, Su, Dongyuan, Cui, Longtao, Kang, Chunsheng. . EPIC-1042 as a potent PTRF/Cavin1-caveolin-1 interaction inhibitor to induce PARP1 autophagic degradation and suppress temozolomide efflux for glioblastoma. In Neuro-oncology, 26, 100-114. doi:10.1093/neuonc/noad159. https://pubmed.ncbi.nlm.nih.gov/37651725/

3. Mancioppi, Valentina, Daffara, Tommaso, Romanisio, Martina, Giordano, Mara, Prodam, Flavia. 2023. A new mutation in the CAVIN1/PTRF gene in two siblings with congenital generalized lipodystrophy type 4: case reports and review of the literature. In Frontiers in endocrinology, 14, 1212729. doi:10.3389/fendo.2023.1212729. https://pubmed.ncbi.nlm.nih.gov/37501786/

4. Liu, Kang-Cheng, Pace, Hudson, Larsson, Elin, Hubert, Madlen, Lundmark, Richard. 2022. Membrane insertion mechanism of the caveola coat protein Cavin1. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2202295119. doi:10.1073/pnas.2202295119. https://pubmed.ncbi.nlm.nih.gov/35696574/

5. Tillu, Vikas A, Rae, James, Gao, Ya, Parton, Robert G, Collins, Brett M. 2021. Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation. In Nature communications, 12, 931. doi:10.1038/s41467-021-21035-4. https://pubmed.ncbi.nlm.nih.gov/33568658/

6. Wei, Zhuang, Lei, Jigang, Shen, Feng, Liao, Kan, Hong, Shangyu. 2020. Cavin1 Deficiency Causes Disorder of Hepatic Glycogen Metabolism and Neonatal Death by Impacting Fenestrations in Liver Sinusoidal Endothelial Cells. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 7, 2000963. doi:10.1002/advs.202000963. https://pubmed.ncbi.nlm.nih.gov/33042738/