Styxl1, or Serine/threonine/tyrosine-interacting-like protein 1, is a pseudophosphatase belonging to the dual-specificity phosphatases family [2,3]. It is involved in multiple biological processes and signaling pathways. In sperm formation, it is a germ-cell specific co-factor of the CCT complex, crucial for flagellar tubulin folding and sperm motility, thus being essential for male fertility [1]. In cellular trafficking, it regulates the trafficking of β-glucocerebrosidase to lysosomes and lysosome function [2]. It also plays roles in stress granule formation, neurite formation, and apoptosis in different cell types [2].

In a Styxl1 knockout (KO) mouse model, deletion of Styxl1 led to male infertility and microtubule defects of sperm flagella. Proteomic analysis of Styxl1 -/- sperm showed abnormal down-regulation of flagella-related proteins including tubulins. Styxl1 deletion also caused defects in CCT complex assembly and tubulin polymerization, revealing its vital role in CCT-facilitated tubulin folding and sperm flagella development [1]. In cell lines, knockdown of Styxl1 enhanced the trafficking of β-glucocerebrosidase and its lysosomal activity, along with changes in endoplasmic reticulum, late endosome, and lysosome compartments, and nuclear translocation of unfolded protein response and lysosomal biogenesis transcription factors [2]. In glioma and hepatocellular carcinoma cell studies, silencing Styxl1 inhibited cell growth, colony formation, migration, invasion, proliferation, and xenograft tumor growth, indicating its oncogenic potential in these cancers [3,4].

In conclusion, Styxl1 is essential for sperm flagella development, cellular trafficking, and lysosome function. The KO and knockdown models have been instrumental in revealing its role in male infertility, lysosome-storage disorders, and cancer. Understanding Styxl1's functions provides insights into the underlying mechanisms of these biological processes and disease conditions, potentially guiding future therapeutic strategies.

References:

1. Chen, Yu, Luo, Mengjiao, Tu, Haixia, Li, Yan, Guo, Xuejiang. 2024. STYXL1 regulates CCT complex assembly and flagellar tubulin folding in sperm formation. In Nature communications, 15, 44. doi:10.1038/s41467-023-44337-1. https://pubmed.ncbi.nlm.nih.gov/38168070/

2. Patel, Saloni, Bhatt, Anshul Milap, Bhansali, Priyanka, Setty, Subba Rao Gangi. 2023. Pseudophosphatase STYXL1 depletion enhances glucocerebrosidase trafficking to lysosomes via ER stress. In Traffic (Copenhagen, Denmark), 24, 254-269. doi:10.1111/tra.12886. https://pubmed.ncbi.nlm.nih.gov/37198709/

3. Tomar, Vivek Singh, Baral, Tapan Kumar, Nagavelu, Krishnaveni, Somasundaram, Kumaravel. 2019. Serine/threonine/tyrosine-interacting-like protein 1 (STYXL1), a pseudo phosphatase, promotes oncogenesis in glioma. In Biochemical and biophysical research communications, 515, 241-247. doi:10.1016/j.bbrc.2019.05.093. https://pubmed.ncbi.nlm.nih.gov/31146910/

4. Wu, J-Z, Jiang, N, Lin, J-M, Liu, X. . STYXL1 promotes malignant progression of hepatocellular carcinoma via downregulating CELF2 through the PI3K/Akt pathway. In European review for medical and pharmacological sciences, 24, 2977-2985. doi:10.26355/eurrev_202003_20662. https://pubmed.ncbi.nlm.nih.gov/32271415/