Herpud1-KO Mouse

Herpud1, also known as homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1, is an endoplasmic reticulum membrane protein involved in maintaining intracellular Ca2+ homeostasis under stress conditions. It is part of the endoplasmic reticulum-associated degradation (ERAD) complex and participates in inositol 1,4,5-trisphosphate receptor (IP3R) degradation and Ca2+ signaling [2,4]. Herpud1 is also an important early marker of endoplasmic reticulum stress (ERS) and is involved in the ubiquitination and degradation of several unfolded proteins [3].

In Herpud1-knockout mice, there is cardiac hypertrophy and dysfunction, along with elevated levels of hypertrophic markers and IP3R in cardiomyocytes, indicating Herpud1 is a negative regulator of pathological cardiac hypertrophy [4]. Herpud1 -deficient mice also display glucose intolerance without altered insulin secretion, and Herpud1 silencing in L6 myotubes decreases insulin-dependent glucose uptake, suggesting its importance in insulin-dependent glucose disposal in skeletal muscle [5]. In a mouse model of homocysteine-induced atherosclerosis, Herpud1 knockout reduces amyloid-β40 expression, inflammation, and oxidative stress, alleviating atherosclerosis via JNK/AP1 signaling inhibition [6]. Also, Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification in mice, as Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of aortic valve interstitial cells (AVICs) [1].

In conclusion, Herpud1 plays crucial roles in multiple biological processes and disease conditions. Studies using Herpud1 knockout mouse models have revealed its significance in cardiac function, glucose metabolism, and several cardiovascular-related diseases such as cardiac hypertrophy, aortic valve calcification, and atherosclerosis. Understanding Herpud1's functions provides potential therapeutic targets for these diseases.

References:

1. Xie, Wenqing, Shan, Yue, Wu, Zhuonan, Lin, Hui, Guo, Hangyuan. 2023. Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification. In Cell biology and toxicology, 39, 2665-2684. doi:10.1007/s10565-023-09794-w. https://pubmed.ncbi.nlm.nih.gov/36746840/

2. Paredes, Felipe, Navarro-Marquez, Mario, Quiroga, Clara, San Martin, Alejandra, Lavandero, Sergio. 2023. HERPUD1 governs tumor cell mitochondrial function via inositol 1,4,5-trisphosphate receptor-mediated calcium signaling. In Free radical biology & medicine, 211, 24-34. doi:10.1016/j.freeradbiomed.2023.11.022. https://pubmed.ncbi.nlm.nih.gov/38043868/

3. Nie, Xin, Liu, Dawo, Zheng, Mingjun, Zhu, Liancheng, Lin, Bei. 2022. HERPUD1 promotes ovarian cancer cell survival by sustaining autophagy and inhibit apoptosis via PI3K/AKT/mTOR and p38 MAPK signaling pathways. In BMC cancer, 22, 1338. doi:10.1186/s12885-022-10248-5. https://pubmed.ncbi.nlm.nih.gov/36544104/

4. Torrealba, Natalia, Navarro-Marquez, Mario, Garrido, Valeria, Kokame, Koichi, Lavandero, Sergio. 2017. Herpud1 negatively regulates pathological cardiac hypertrophy by inducing IP3 receptor degradation. In Scientific reports, 7, 13402. doi:10.1038/s41598-017-13797-z. https://pubmed.ncbi.nlm.nih.gov/29042597/

5. Navarro-Marquez, Mario, Torrealba, Natalia, Troncoso, Rodrigo, Kokame, Koichi, Lavandero, Sergio. 2018. Herpud1 impacts insulin-dependent glucose uptake in skeletal muscle cells by controlling the Ca2+-calcineurin-Akt axis. In Biochimica et biophysica acta. Molecular basis of disease, 1864, 1653-1662. doi:10.1016/j.bbadis.2018.02.018. https://pubmed.ncbi.nlm.nih.gov/29486284/

6. Gao, Feidan, Zhang, Jie, Ni, Tingjuan, Guo, Hangyuan, Chi, Jufang. 2020. Herpud1 deficiency could reduce amyloid-β40 expression and thereby suppress homocysteine-induced atherosclerosis by blocking the JNK/AP1 pathway. In Journal of physiology and biochemistry, 76, 383-391. doi:10.1007/s13105-020-00741-5. https://pubmed.ncbi.nlm.nih.gov/32488540/