Wdfy1, the WD repeat and FYVE domain containing 1 gene, encodes a 410-amino-acid protein sharing 97.8% amino-acid sequence identity with the human WDFY1 protein. It is involved in several key biological processes. Wdfy1 is a crucial adaptor protein in the TLR3/4 signaling pathway, mediating the recruitment of TRIF to these receptors, thus playing a role in the innate immune response [3]. It is also part of the CUL4A-DDB1-WDFY1 E3 ubiquitin ligase complex essential for initiating lysophagy to clear damaged lysosomes [4].

In gene-knockout studies, global Wdfy1 knockout male mice showed normal growth, development, and fertility, indicating that WDFY1 is dispensable for mouse spermatogenesis and male fertility [1]. Wdfy1-deficient mice displayed impaired Tlr3-mediated immune responses in vivo [2]. In the cGVHD mouse model of lupus, Wdfy1-knockout led to reduced auto-antibody response due to impaired normal functioning of follicular dendritic cells which express high levels of WDFY1 required for immune complex presentation [5].

In conclusion, Wdfy1 is involved in multiple biological functions such as immune response, lysophagy, and endocytic/vacuolar membrane trafficking. Gene-knockout mouse models have been instrumental in revealing its non-essential role in spermatogenesis and male fertility, as well as its importance in the immune response and lupus-related auto-antibody production. These findings contribute to our understanding of the biological processes and disease mechanisms associated with Wdfy1.

References:

1. Lv, Chunyu, Xiong, Mengneng, Guo, Shuangshuang, Qin, Weibing, Yuan, Shuiqiao. 2022. WDFY1, a WD40 repeat protein, is not essential for spermatogenesis and male fertility in mice. In Biochemical and biophysical research communications, 596, 71-75. doi:10.1016/j.bbrc.2022.01.084. https://pubmed.ncbi.nlm.nih.gov/35121371/

2. Yang, Yang, Hu, Yun-Hong, Liu, Yu. 2020. Wdfy1 deficiency impairs Tlr3-mediated immune responses in vivo. In Cellular & molecular immunology, 17, 1014-1016. doi:10.1038/s41423-020-0461-4. https://pubmed.ncbi.nlm.nih.gov/32398807/

3. Hu, Yun-Hong, Zhang, Yu, Jiang, Li-Qun, Shu, Hong-Bing, Liu, Yu. 2015. WDFY1 mediates TLR3/4 signaling by recruiting TRIF. In EMBO reports, 16, 447-55. doi:10.15252/embr.201439637. https://pubmed.ncbi.nlm.nih.gov/25736436/

4. Teranishi, Hirofumi, Tabata, Keisuke, Saeki, Marika, Yoshimori, Tamotsu, Hamasaki, Maho. . Identification of CUL4A-DDB1-WDFY1 as an E3 ubiquitin ligase complex involved in initiation of lysophagy. In Cell reports, 40, 111349. doi:10.1016/j.celrep.2022.111349. https://pubmed.ncbi.nlm.nih.gov/36103833/

5. Zhen, Yuxuan, Shao, Wen-Hai. 2025. WDFY1-expressing follicular dendritic cells play a critical role in lupus development in cGVHD mouse model. In Journal of immunology (Baltimore, Md. : 1950), , . doi:10.1093/jimmun/vkaf017. https://pubmed.ncbi.nlm.nih.gov/40169152/