Arl15, an ADP-ribosylation factor-like GTPase, is a member of the RAS superfamily of small GTPases [3]. It has been associated with multiple metabolic traits such as increased risk of diabetes, rheumatoid arthritis, and lipid metabolism disorders [3]. Functionally, it is involved in diverse biological processes. It modulates magnesium (Mg2+) homeostasis by promoting complex N-glycosylation of CNNMs, acting as a negative regulator of Mg2+ transport [1]. Arl15 also upregulates the TGFβ family signaling by facilitating the assembly of the Smad-complex [2].

In a mouse global Arl15 gene knockout, homozygotes were postnatal lethal and had a complete cleft palate. Heterozygous females had reduced fat mass on a chow diet from 14 weeks of age, and on a high-fat diet, they showed reduced body weight, gonadal fat depot weight, and brown adipose tissue weight. In contrast, on a low-fat diet, females had increased bone mineral density while males showed a trend toward reduced BMD [4].

In conclusion, Arl15 is essential for craniofacial development. Its roles in brown adipose tissue and bone development are also emerging from mouse knockout models. Its association with metabolic traits and diseases like diabetes and rheumatoid arthritis suggests it could be a potential therapeutic target in these disease areas [3,4].

References:

1. Zolotarov, Yevgen, Ma, Chao, González-Recio, Irene, Tremblay, Michel L, de Baaij, Jeroen H F. 2021. ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs. In Cellular and molecular life sciences : CMLS, 78, 5427-5445. doi:10.1007/s00018-021-03832-8. https://pubmed.ncbi.nlm.nih.gov/34089346/

2. Shi, Meng, Tie, Hieng Chiong, Divyanshu, Mahajan, Vardy, Leah A, Lu, Lei. 2022. Arl15 upregulates the TGFβ family signaling by promoting the assembly of the Smad-complex. In eLife, 11, . doi:10.7554/eLife.76146. https://pubmed.ncbi.nlm.nih.gov/35834310/

3. Saini, Manisha, Anand, Varnita, Sharma, Aditya, Thelma, Bittianda Kuttapa, Kundu, Suman. . ARL15 and its Multiple Disease Association: Emerging Functions and Potential Therapeutic Application. In Current protein & peptide science, 25, 137-153. doi:10.2174/1389203724666230915123217. https://pubmed.ncbi.nlm.nih.gov/37718516/

4. Bai, Ying, Bentley, Liz, Ma, Chao, de Baaij, Jeroen H F, Cox, Roger D. . Cleft palate and minor metabolic disturbances in a mouse global Arl15 gene knockout. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37, e23211. doi:10.1096/fj.202201918R. https://pubmed.ncbi.nlm.nih.gov/37773757/