Hectd1, the HECT domain E3 ubiquitin ligase 1, plays crucial roles in various biological processes. It is involved in pathways related to ribosome assembly, autophagy, and epithelial-mesenchymal transition (EMT), which are vital for normal cell function, development, and disease prevention [1,2,4]. Genetic models, such as knockout mouse models, are valuable for studying its functions.

In Hectd1-deficient hematopoietic stem cells (HSCs), there is a defect in transplantation ability and ex vivo maintenance due to reduced protein synthesis from ribosomal subunit joining defects. Hectd1 ubiquitinates and degrades ZNF622, an assembly factor for the ribosomal 60S subunit, and its loss leads to 60S/40S joining defects [1]. In osteoarthritis, HECTD1 down-regulation was observed in human OA cartilage samples. Overexpression in mouse joints alleviated OA, while conditional depletion in cartilage aggravated OA pathogenesis. HECTD1 binds to and ubiquitinates Rubicon at lysine residue 534 for proteasomal degradation, regulating chondrocyte autophagy [2]. Hectd1-mutant homozygous mice showed early embryonic lethality with abnormal placental development and neural tube closure defects [3]. Knockdown of HECTD1 in HeLa cells increased cell migration, induced a mesenchymal phenotype, and sustained EGF signaling, suggesting its role in regulating EMT [4].

In conclusion, Hectd1 is essential for embryogenesis, HSC regeneration, and the regulation of autophagy and EMT. Gene knockout mouse models have revealed its significance in diseases like osteoarthritis and potentially in cancer-related EMT processes, contributing to our understanding of disease mechanisms and highlighting its potential as a therapeutic target.

References:

1. Lv, Kaosheng, Gong, Chujie, Antony, Charles, Paralkar, Vikram R, Tong, Wei. 2021. HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis. In Cell stem cell, 28, 1275-1290.e9. doi:10.1016/j.stem.2021.02.008. https://pubmed.ncbi.nlm.nih.gov/33711283/

2. Liao, Shiyao, Zheng, Qiangqiang, Shen, Haotian, Ouyang, Hongwei, Pan, Zongyou. 2023. HECTD1-Mediated Ubiquitination and Degradation of Rubicon Regulates Autophagy and Osteoarthritis Pathogenesis. In Arthritis & rheumatology (Hoboken, N.J.), 75, 387-400. doi:10.1002/art.42369. https://pubmed.ncbi.nlm.nih.gov/36121967/

3. D'Alonzo, Donato, Emch, Fabienne Hélène, Shen, Xiaoli, De Geyter, Christian, Zhang, Hong. 2019. Hectd1 is essential for embryogenesis in mice. In Gene expression patterns : GEP, 34, 119064. doi:10.1016/j.gep.2019.119064. https://pubmed.ncbi.nlm.nih.gov/31301385/

4. Wang, Xinggang, De Geyter, Christian, Jia, Zanhui, Peng, Ya, Zhang, Hong. 2020. HECTD1 regulates the expression of SNAIL: Implications for epithelial‑mesenchymal transition. In International journal of oncology, 56, 1186-1198. doi:10.3892/ijo.2020.5002. https://pubmed.ncbi.nlm.nih.gov/32319576/