Hspa8, also known as HSC70, is a constitutively expressed, cognate protein of the HSP70 family. It is central in many cellular processes, particularly playing a decisive regulatory role in autophagy. It is involved in protein quality control, ensuring proper protein folding and the elimination of mis-folded proteins [2,8].

Research shows that Hspa8 has multiple functions. It regulates anti-bacterial autophagy by binding to RHOB and BECN1, preventing their degradation and driving liquid-liquid phase separation to enhance their interaction, thus clearing intracellular bacteria [1]. Hspa8 acts as an amyloidase, directly disassembling RHIM-amyloids to inhibit necroptosis signaling in cells and mice [3]. In liver cancer, HBx-induced Hspa8 stimulates HBV replication and suppresses ferroptosis, promoting liver cancer progression [4]. In BRAF V600E colorectal cancer, Hspa8 activates the Wnt/β-catenin pathway by promoting CMA-mediated CAV1 degradation, contributing to cancer metastasis and progression [5]. RPL35A promotes cholangiocarcinoma progression by mediating Hspa8 ubiquitination [6]. The lncRNA MAGI2-AS3 regulates the H2O2 level and cell senescence via Hspa8 [7]. PRMT9-mediated arginine methylation of Hspa8 inhibits ferroptosis, accelerating hepatitis B virus-associated hepatocellular carcinoma progression [9]. BAG5 is essential for sperm head-tail coupling apparatus assembly as it promotes Hspa8-mediated folding of relevant proteins [10].

In conclusion, Hspa8 is crucial in various biological processes such as autophagy, anti-bacterial defense, and in diseases like liver cancer, colorectal cancer, cholangiocarcinoma, and male infertility. Its study using genetic models helps understand the underlying mechanisms of these diseases, potentially providing new therapeutic targets.

References:

1. Miao, Chunhui, Zhang, Yajie, Yu, Mingyu, Yao, Zhi, Wang, Quan. 2023. HSPA8 regulates anti-bacterial autophagy through liquid-liquid phase separation. In Autophagy, 19, 2702-2718. doi:10.1080/15548627.2023.2223468. https://pubmed.ncbi.nlm.nih.gov/37312409/

2. Stricher, François, Macri, Christophe, Ruff, Marc, Muller, Sylviane. 2013. HSPA8/HSC70 chaperone protein: structure, function, and chemical targeting. In Autophagy, 9, 1937-54. doi:10.4161/auto.26448. https://pubmed.ncbi.nlm.nih.gov/24121476/

3. Wu, Erpeng, He, Wenyan, Wu, Chenlu, Wang, Sheng, Sun, Liming. 2023. HSPA8 acts as an amyloidase to suppress necroptosis by inhibiting and reversing functional amyloid formation. In Cell research, 33, 851-866. doi:10.1038/s41422-023-00859-3. https://pubmed.ncbi.nlm.nih.gov/37580406/

4. Wang, Yufei, Zhao, Man, Zhao, Lina, Lu, Wei, Zhang, Xiaodong. . HBx-Induced HSPA8 Stimulates HBV Replication and Suppresses Ferroptosis to Support Liver Cancer Progression. In Cancer research, 83, 1048-1061. doi:10.1158/0008-5472.CAN-22-3169. https://pubmed.ncbi.nlm.nih.gov/36745032/

5. Li, Bowen, Ming, Hui, Qin, Siyuan, Jiang, Jingwen, Huang, Canhua. 2023. HSPA8 Activates Wnt/β-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2306535. doi:10.1002/advs.202306535. https://pubmed.ncbi.nlm.nih.gov/37973552/

6. Zhang, Chengshuo, Wang, Yu, Wu, Gang, Qi, Ruizhao, Zhang, Jialin. 2024. RPL35A promotes the progression of cholangiocarcinoma by mediating HSPA8 ubiquitination. In Biology direct, 19, 16. doi:10.1186/s13062-024-00453-6. https://pubmed.ncbi.nlm.nih.gov/38395908/

7. Zhang, Yingmin, Qiao, Xinhua, Liu, Lihui, Chen, Runsheng, Chen, Chang. 2022. Long noncoding RNA MAGI2-AS3 regulates the H2O2 level and cell senescence via HSPA8. In Redox biology, 54, 102383. doi:10.1016/j.redox.2022.102383. https://pubmed.ncbi.nlm.nih.gov/35797800/

8. Bonam, Srinivasa Reddy, Ruff, Marc, Muller, Sylviane. 2019. HSPA8/HSC70 in Immune Disorders: A Molecular Rheostat that Adjusts Chaperone-Mediated Autophagy Substrates. In Cells, 8, . doi:10.3390/cells8080849. https://pubmed.ncbi.nlm.nih.gov/31394830/

9. Deng, Wensheng, Ai, Jiaoyu, Zhang, Wanlin, Ai, Junhua, Jiang, Hai. 2023. Arginine methylation of HSPA8 by PRMT9 inhibits ferroptosis to accelerate hepatitis B virus-associated hepatocellular carcinoma progression. In Journal of translational medicine, 21, 625. doi:10.1186/s12967-023-04408-9. https://pubmed.ncbi.nlm.nih.gov/37715221/

10. 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/