Ubl3, also known as Ubiquitin-like 3, is a membrane-anchored protein and a type of ubiquitin-like protein (UBL). It serves as a post-translational modification factor and plays a crucial role in sorting proteins into small extracellular vesicles (sEVs). Ubl3 is involved in multiple biological processes, such as the ubiquitin cascade, and is associated with pathways related to immune responses, neurodegenerative diseases, and cancer [1,4,7]. Genetic models, like mouse models, are valuable for studying its functions.

In Ubl3-deficient mice, elevated MHC II and CD86 expression was observed on the surface of professional and atypical antigen-presenting cells. This indicates that Ubl3 is required for MARCH ubiquitination of major histocompatibility complex class II and CD86, and loss of Ubl3 alters adaptive immunity with impaired development of thymic regulatory T cells, loss of conventional type 1 DCs, increased number of trogocytic marginal zone B cells, and defective in vivo MHC II and MHC I antigen presentation [2]. Also, in Ubl3-knockout mice, there was a 60% reduction of total protein levels in sEVs compared to wild-type mice, suggesting its importance in protein sorting to sEVs [4].

In conclusion, Ubl3 is essential for protein sorting to sEVs and for MARCH-mediated ubiquitination in immune responses. Studies using Ubl3-KO mouse models have provided insights into its role in immune-related diseases and the molecular mechanisms of protein sorting. This knowledge contributes to understanding disease pathophysiology and may lead to the development of new therapeutic strategies for diseases such as neurodegenerative disorders and cancer [1,2,3,5,6].

References:

1. Zhang, Hengsen, Chen, Bin, Waliullah, A S M, Kahyo, Tomoaki, Setou, Mitsutoshi. 2023. A New Potential Therapeutic Target for Cancer in Ubiquitin-Like Proteins-UBL3. In International journal of molecular sciences, 24, . doi:10.3390/ijms24021231. https://pubmed.ncbi.nlm.nih.gov/36674743/

2. Liu, Haiyin, Wilson, Kayla R, Firth, Ashley M, Villadangos, Jose A, Mintern, Justine D. 2022. Ubiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86. In Nature communications, 13, 1934. doi:10.1038/s41467-022-29524-w. https://pubmed.ncbi.nlm.nih.gov/35411049/

3. Chen, Bin, Hasan, Md Mahmudul, Zhang, Hengsen, Yoshida, Minoru, Setou, Mitsutoshi. 2023. UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib. In Biomedicines, 11, . doi:10.3390/biomedicines11061685. https://pubmed.ncbi.nlm.nih.gov/37371780/

4. Ageta, Hiroshi, Ageta-Ishihara, Natsumi, Hitachi, Keisuke, Setou, Mitsutoshi, Tsuchida, Kunihiro. 2018. UBL3 modification influences protein sorting to small extracellular vesicles. In Nature communications, 9, 3936. doi:10.1038/s41467-018-06197-y. https://pubmed.ncbi.nlm.nih.gov/30258067/

5. Oyama, Soho, Zhang, Hengsen, Ferdous, Rafia, Kaneda, Daita, Setou, Mitsutoshi. 2024. UBL3 Interacts with PolyQ-Expanded Huntingtin Fragments and Modifies Their Intracellular Sorting. In Neurology international, 16, 1175-1188. doi:10.3390/neurolint16060089. https://pubmed.ncbi.nlm.nih.gov/39449505/

6. Mimi, Mst Afsana, Hasan, Md Mahmudul, Takanashi, Yusuke, Koizumi, Kei, Setou, Mitsutoshi. 2024. UBL3 overexpression enhances EV-mediated Achilles protein secretion in conditioned media of MDA-MB-231 cells. In Biochemical and biophysical research communications, 738, 150559. doi:10.1016/j.bbrc.2024.150559. https://pubmed.ncbi.nlm.nih.gov/39182355/

7. Takanashi, Yusuke, Kahyo, Tomoaki, Kamamoto, Sae, Shiiya, Norihiko, Setou, Mitsutoshi. . Ubiquitin-like 3 as a new protein-sorting factor for small extracellular vesicles. In Cell structure and function, 47, 1-18. doi:10.1247/csf.21078. https://pubmed.ncbi.nlm.nih.gov/35197392/