Sec24a-KO Mouse

Sec24a, SEC24 homolog A, COPII coat complex component, is a crucial part of the COPII coat involved in the packaging of cargo proteins into COPII-coated vesicles for the transport from the endoplasmic reticulum (ER) to the Golgi in eukaryotic cells [2,3,4,5]. This process is fundamental for normal cellular function, and the gene's role in this pathway underscores its biological importance. Genetic models, such as knockout mouse models, have been instrumental in studying its functions.

In mice, SEC24A-deficient animals exhibit reduced plasma cholesterol due to decreased PCSK9 secretion, as PCSK9 depends on SEC24A for efficient ER exit, and this leads to up-regulation of hepatic LDLR levels [2]. In HAP1 cells, knockout of SEC24A impairs Ca2+ efflux from the ER and influx into mitochondria, reducing their colocalization by ∼44%. This knockout also rescues cells from cell death induced by three different inhibitors of sarcoplasmic/endoplasmic reticulum Ca2+ ATPases, while increasing autophagic flux ∼2.5-fold and reducing apoptosis ∼10-fold compared to wild-type cells [1].

In summary, Sec24a is essential for ER-to-Golgi transport. Model-based research, especially through knockout models, has revealed its role in regulating cholesterol metabolism, ER-mitochondria communication, and cell death-related processes. These findings contribute to understanding diseases related to abnormal cholesterol levels, ER stress-induced cell death, and potentially autophagy-and apoptosis-related pathologies [1,2].

References:

1. Chidawanyika, Tamutenda, Chakrabarti, Rajarshi, Beauchemin, Kathryn S, Higgs, Henry N, Supattapone, Surachai. 2021. SEC24A facilitates colocalization and Ca2+ flux between the endoplasmic reticulum and mitochondria. In Journal of cell science, 134, . doi:10.1242/jcs.249276. https://pubmed.ncbi.nlm.nih.gov/33622772/

2. Chen, Xiao-Wei, Wang, He, Bajaj, Kanika, Schekman, Randy, Ginsburg, David. 2013. SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. In eLife, 2, e00444. doi:10.7554/eLife.00444. https://pubmed.ncbi.nlm.nih.gov/23580231/

3. Qu, Xian, Chatty, Prerana Rao, Roeder, Adrienne H K. 2014. Endomembrane trafficking protein SEC24A regulates cell size patterning in Arabidopsis. In Plant physiology, 166, 1877-90. doi:10.1104/pp.114.246033. https://pubmed.ncbi.nlm.nih.gov/25315606/

4. Conger, Renata, Chen, Yani, Fornaciari, Silvia, Renna, Luciana, Brandizzi, Federica. 2011. Evidence for the involvement of the Arabidopsis SEC24A in male transmission. In Journal of experimental botany, 62, 4917-26. doi:10.1093/jxb/err174. https://pubmed.ncbi.nlm.nih.gov/21705385/

5. Nakano, Ryohei Thomas, Matsushima, Ryo, Ueda, Haruko, Nishimura, Mikio, Hara-Nishimura, Ikuko. 2009. GNOM-LIKE1/ERMO1 and SEC24a/ERMO2 are required for maintenance of endoplasmic reticulum morphology in Arabidopsis thaliana. In The Plant cell, 21, 3672-85. doi:10.1105/tpc.109.068270. https://pubmed.ncbi.nlm.nih.gov/19933201/