BAG5, also known as Bcl-2 associated anthanogene 5, is a co-chaperone protein. It belongs to the BAG family and has a unique structure with multiple domains. BAG5 is involved in protein quality control (PQC) pathways, interacting with heat shock proteins like HSPA8 (HSP70) to assist in protein folding [2]. It also plays a role in various biological processes such as mitophagy, endoplasmic stress response, and cell viability regulation [2]. Genetic models, especially mouse models, have been crucial in studying BAG5's functions.

In male infertility research, BAG5-deficient male mice show abnormal assembly of the sperm head-tail coupling apparatus (HTCA), leading to acephalic spermatozoa syndrome (ASS) and male infertility, similar to SPATA6-deficient mice. Mechanistically, BAG5 forms a complex with HSPA8 and promotes the folding of SPATA6, cargo transport-related myosin and dynein proteins, which are misfolded upon BAG5 depletion [1]. In a study on a novel BAG5 variant, homozygous Bag5 -/- mice showed no abnormalities up to 12 months old but had significantly reduced left ventricular fractional shortening (LVFS) and ejection fraction (LVEF) after tunicamycin (TN) injection, indicating that the BAG5 mutation impairs the ER stress response, causing dilated cardiomyopathy and arrhythmia [3].

In conclusion, BAG5 is essential for protein folding and quality control in cells. Model-based research, especially using gene-knockout mouse models, has revealed its critical roles in male infertility and cardiovascular diseases such as dilated cardiomyopathy. Understanding BAG5's functions provides insights into the underlying mechanisms of these diseases and may offer potential therapeutic targets.

References:

1. Gan, Shiming, Zhou, Shumin, Ma, Jinzhe, Ma, Meisheng, Yuan, Shuiqiao. 2024. BAG5 regulates HSPA8-mediated protein folding required for sperm head-tail coupling apparatus assembly. In EMBO reports, 25, 2045-2070. doi:10.1038/s44319-024-00112-x. https://pubmed.ncbi.nlm.nih.gov/38454159/

2. Gupta, Manish K, Randhawa, Puneet Kaur, Masternak, Michal M. 2022. Role of BAG5 in Protein Quality Control: Double-Edged Sword? In Frontiers in aging, 3, 844168. doi:10.3389/fragi.2022.844168. https://pubmed.ncbi.nlm.nih.gov/35821856/

3. Wongong, Rutairat, Kijtawornrat, Anusak, Srichomthong, Chalurmpon, Porntaveetus, Thantrira, Shotelersuk, Vorasuk. 2024. A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia. In Scientific reports, 14, 11980. doi:10.1038/s41598-024-62764-y. https://pubmed.ncbi.nlm.nih.gov/38796549/