Arl6ip5, also known as JWA, is an endoplasmic reticulum-localized protein belonging to the prenylated rab-acceptor-family. It plays diverse roles in various physiological and pathological processes. It is involved in exocytic protein trafficking, glutathione metabolism, and is associated with pathways like autophagy, apoptosis, and ER stress response, which are crucial for maintaining cellular homeostasis and are implicated in multiple diseases [2,3,4,5].

In ovarian carcinoma, ARL6IP5 overexpression reduces cisplatin-resistance by suppressing DNA repair proteins (such as XRCC1 and PARP1) and promoting apoptosis, while knockdown has the opposite effect. It is also an independent prognosticator for high-grade serous OC patients [1]. In neurodegenerative diseases, Arl6ip5 levels decrease in the brain with age and in Parkinson's disease. Overexpression of ARL6IP5 reduces α-synuclein aggregate burden by inducing autophagy via preventing ubiquitination and degradation of ATG12 [2]. In a cellular prion disease model, ARL6IP5 is upregulated in response to chronically activated unfolded protein response (UPR), and its overexpression induces reticulophagy to reduce the prion protein burden by alleviating ER stress [3]. In bone, Arl6ip5 knockout mice show decreased bone mineral density. Osteoblastic Arl6ip5 deficiency impairs osteoblast differentiation and enhances osteoclastogenesis through disturbing ER calcium homeostasis and inducing ER stress-mediated apoptosis [5].

In conclusion, Arl6ip5 is a multi-functional gene involved in autophagy, apoptosis, ER stress response, and protein trafficking, which are associated with diseases such as ovarian carcinoma, neurodegenerative diseases, and bone-related disorders. Gene knockout mouse models have been instrumental in revealing its role in these biological processes and disease conditions, providing valuable insights into potential therapeutic targets for these diseases.

References:

1. Kim, Ji-Ye, Bahar, Entaz, Lee, Jung-Yun, Yoon, Hyonok, Kim, Hyun-Soo. 2022. ARL6IP5 reduces cisplatin-resistance by suppressing DNA repair and promoting apoptosis pathways in ovarian carcinoma. In Cell death & disease, 13, 239. doi:10.1038/s41419-022-04568-4. https://pubmed.ncbi.nlm.nih.gov/35293383/

2. Siddique, Ibrar, Kamble, Kajal, Gupta, Sakshi, Ahsan, Nuzhat, Gupta, Sarika. 2023. ARL6IP5 Ameliorates α-Synuclein Burden by Inducing Autophagy via Preventing Ubiquitination and Degradation of ATG12. In International journal of molecular sciences, 24, . doi:10.3390/ijms241310499. https://pubmed.ncbi.nlm.nih.gov/37445677/

3. Kamble, Kajal, Kumar, Ujjwal, Aahra, Harsh, Bhola, Sumnil, Gupta, Sarika. 2024. A novel ER stress regulator ARL6IP5 induces reticulophagy to ameliorate the prion burden. In Autophagy, 21, 598-618. doi:10.1080/15548627.2024.2410670. https://pubmed.ncbi.nlm.nih.gov/39394963/

4. Wu, Yu, Wang, Miaomiao, Peng, Ying, Deng, Lili, Fu, Qiang. 2015. Overexpression of Arl6ip5 in osteoblast regulates RANKL subcellualr localization. In Biochemical and biophysical research communications, 464, 1275-1281. doi:10.1016/j.bbrc.2015.07.119. https://pubmed.ncbi.nlm.nih.gov/26220341/

5. Wu, Y, Yang, M, Fan, J, Miao, D, Fu, Q. 2014. Deficiency of osteoblastic Arl6ip5 impaired osteoblast differentiation and enhanced osteoclastogenesis via disturbance of ER calcium homeostasis and induction of ER stress-mediated apoptosis. In Cell death & disease, 5, e1464. doi:10.1038/cddis.2014.427. https://pubmed.ncbi.nlm.nih.gov/25321471/