Iqub, encoding the IQUB protein with an IQ motif and ubiquitin-like domain, is highly and specifically expressed in murine testes. It is involved in the assembly of sperm radial spokes, a crucial structure for sperm motility. The protein interacts with RSPH3, CEP295NL, GSTM1, and ODF1, and may be related to pathways such as those involving p-ERK1/2 and calmodulin recruitment [1].

Gene knockout (KO) and knock-in (KI) mouse models were constructed to study Iqub's function. In both KO and KI mice, sperm had radial spoke defects, mimicking the infertility phenotype seen in human patients with IQUB variants. Functional assays suggested that IQUB inhibits the activity of RSPH3/p-ERK1/2 to facilitate normal radial spoke assembly by recruiting calmodulin in lower Ca2+ environments [1]. Another study with an Iqub-deficient mouse model showed that sperm flagella lacked the entire RS1, while tracheal cilia had intact triple RSs, resulting in male infertility due to sperm motility defects [2]. Additionally, in Iqub -/- mice, a deficiency of RS1 but not RS2 or RS3 was observed, leading to reduced sperm kinetic parameters [3].

In conclusion, Iqub plays an essential role in the assembly of sperm radial spoke 1 and sperm motility. The KO and KI mouse models have been instrumental in revealing its function in male infertility, expanding our understanding of the genetic factors contributing to asthenospermia and potentially providing a new genetic marker for male infertility [1,2,3].

References:

1. Zhang, Zhihua, Zhou, Hongbin, Deng, Xujing, Sang, Qing, Bao, Shihua. . IQUB deficiency causes male infertility by affecting the activity of p-ERK1/2/RSPH3. In Human reproduction (Oxford, England), 38, 168-179. doi:10.1093/humrep/deac244. https://pubmed.ncbi.nlm.nih.gov/36355624/

2. Zhang, Xin, Xiao, Zhuang, Zhang, Jintao, Wang, Ying, Liu, Mingxi. . Differential requirements of IQUB for the assembly of radial spoke 1 and the motility of mouse cilia and flagella. In Cell reports, 41, 111683. doi:10.1016/j.celrep.2022.111683. https://pubmed.ncbi.nlm.nih.gov/36417862/

3. Hu, Tingwenyi, Tang, Xiangrong, Ruan, Tiechao, Shen, Ying, Lin, Tingting. 2025. IQUB mutation induces radial spoke 1 deficiency causing asthenozoospermia with normal sperm morphology in humans and mice. In Cell communication and signaling : CCS, 23, 41. doi:10.1186/s12964-025-02043-z. https://pubmed.ncbi.nlm.nih.gov/39849482/