Wdfy1, the WD repeat and FYVE domain containing 1 gene, encodes a 410-amino acid protein sharing 97.8% amino acid sequence identity with its human counterpart. It is involved in several key biological pathways. Wdfy1 plays a crucial role in the TLR3/4 signaling pathway as an adaptor protein, bridging the TLR-TRIF interaction, and is also part of the CUL4A-DDB1-WDFY1 E3 ubiquitin ligase complex involved in lysophagy initiation [3,4].

Global Wdfy1 knockout (KO) male mice show normal growth, development, and fertility, indicating that WDFY1 is dispensable for mouse spermatogenesis and male fertility [1]. Wdfy1 deficiency impairs Tlr3-mediated immune responses in vivo [2]. In the cGVHD mouse model, Wdfy1 knockout impairs the normal functioning of follicular dendritic cells, leading to a reduced auto-Ab response to cGVHD [5]. Hes1 attenuates type I IFN responses via WDFY1, with Hes1-deficient mice showing a heightened IFN signature [6]. Also, NRP2 transcriptionally regulates WDFY1, and in ovarian cancer, Wdfy1 expression is increased in Ankrd22-knockout BM-derived CD11b+Ly6G+Ly6Clow cells, affecting the immunosuppressive activity of PMN-MDSCs [7,8].

In summary, Wdfy1 is involved in multiple biological processes including spermatogenesis, immune responses, lysophagy, and regulation of endocytic activity. Gene knockout mouse models have been instrumental in revealing its non-essential role in spermatogenesis and male fertility, as well as its significance in immune-related diseases such as lupus and in modulating the immunosuppressive effects in ovarian cancer. These models help us understand the complex functions of Wdfy1 and its potential implications in disease mechanisms.

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/

6. Ning, Fei, Li, Xiaoyu, Yu, Li, Shang, Yingli, Hu, Xiaoyu. 2019. Hes1 attenuates type I IFN responses via VEGF-C and WDFY1. In The Journal of experimental medicine, 216, 1396-1410. doi:10.1084/jem.20180861. https://pubmed.ncbi.nlm.nih.gov/31015298/

7. Dutta, Samikshan, Roy, Sohini, Polavaram, Navatha S, Batra, Surinder, Datta, Kaustubh. 2016. NRP2 transcriptionally regulates its downstream effector WDFY1. In Scientific reports, 6, 23588. doi:10.1038/srep23588. https://pubmed.ncbi.nlm.nih.gov/27026195/

8. Chen, Huanhuan, Yang, Keqing, Pang, Lingxiao, Zhu, Yongliang, Zhou, Jianwei. . ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs in ovarian cancer. In Journal for immunotherapy of cancer, 11, . doi:10.1136/jitc-2022-005527. https://pubmed.ncbi.nlm.nih.gov/36822671/