UBXD8 is a protein in the Ubiquitin regulatory X (UBX) domain-containing protein family.[1] The UBX domain contains many eukaryotic proteins that have similarities in amino acid sequence to the tiny protein modifier ubiquitin.[2] UBXD8 engages in a molecular interaction with p97,[3] a protein that is essential for the degradation of membrane proteins associated with the endoplasmic reticulum (ER) through the proteasome. [4] Ubxd8 possesses a UBA domain, alongside the UBX domain, that could interact with polyubiquitin chains. [3] Additionally, it possesses a UAS domain of undetermined function, and this protein is used as a protein sensor that detects long chain unsaturated fatty acids (FAs), having a vital function in regulating the balance of Fatty Acids within cells to maintain cellular homeostasis. [5]

Influence of UBXD8 on lipid droplets

The hairpin loop in cell membranes helps Ubxd8 get inside by sensing unsaturated fatty acids (FAs) and controlling the production of triglycerides (TGs).[6] The inhibition of TG synthesis is caused by Ubxd8, which blocks the conversion of diacylglycerols (DAGs) to TGs. However, this inhibition is alleviated when there is an abundance of unsaturated fatty acids. [7] The structure of Ubxd8 is altered by unsaturated FAs, which in turn releases the brake on the synthesis of TG. [8] Ubxd8 contributes to maintaining cellular energy balance by attracting p97/VCP to lipid droplets (LDs) and suppressing the function of adipose triglyceride lipase (ATGL), the enzyme that controls the rate of triacylglycerol breakdown. [9] Moreover, VCP brings UBXD8 to mitochondria, where it participates in the regulation of mitochondrial protein quality. [10] Disruption of UBXD8 gene hinders the breakdown of the pro-survival protein Mcl1 and excessively stimulates the process of mitophagy. To better understand how lipo-toxicity is caused by saturated fatty acids, it might be helpful to learn how Ubxd8 works with unsaturated fatty acids. The inhibitory effect of long-chain unsaturated fatty acids (FAs) on the interaction between Ubxd8 and Insig-1 is due to their ability to obstruct the binding between these two proteins, hence impeding the extraction of Insig-1 from the membrane. [11] This inhibition is independent of the ubiquitination of Insig-1 and occurs after ubiquitination. [12] Without affecting its ubiquitination, unsaturated FAs stabilize Insig-1, and they improve the capacity of sterols to inhibit the proteolytic activation of SREBP-1. [13] The polymerization of the UAS domain of Ubxd8 occurs when it interacts with long-chain unsaturated FAs, which is essential for this process. [14] For the polymerization reaction to be facilitated, the surface area of the UAS domain must be positively charged. The capacity of long-chain unsaturated FAs to stimulate oligomerization of Ubxd8 is hindered by mutations that take place in this specific region. [15]

References

  1. ↑ Imai, Yukiho; Nakada, Akiko; Hashida, Ryoichi; Sugita, Yuji; Tanaka, Toshio; Tsujimoto, Gozoh; Matsumoto, Kenji; Akasawa, Akira; Saito, Hirohisa; Oshida, Tadahilo (October 2002). "Cloning and characterization of the highly expressed ETEA gene from blood cells of atopic dermatitis patients". Biochemical and Biophysical Research Communications. 297 (5): 1282–1290. doi:10.1016/S0006-291X(02)02380-X. PMID 12372427.
  2. ↑ Hofmann, Kay; Bucher, Philipp (May 1996). "The UBA domain: a sequence motif present in multiple enzyme classes of the ubiquitination pathway". Trends in Biochemical Sciences. 21 (5): 172–173. doi:10.1016/s0968-0004(96)30015-7. ISSN 0968-0004. PMID 8871400.
  3. 1 2 Buchberger, A (2002-05-01). "From UBA to UBX: new words in the ubiquitin vocabulary". Trends in Cell Biology. 12 (5): 216–221. doi:10.1016/S0962-8924(02)02269-9. PMID 12062168.
  4. ↑ Kim, Hyeonwoo; Zhang, Hong; Meng, David; Russell, Geoffrey; Lee, Joon No; Ye, Jin (August 2013). "UAS domain of Ubxd8 and FAF1 polymerizes upon interaction with long-chain unsaturated fatty acids". Journal of Lipid Research. 54 (8): 2144–2152. doi:10.1194/jlr.M037218. PMC 3708364. PMID 23720822.
  5. ↑ Halawani, Dalia; Latterich, Martin (June 2006). "p97: The Cell's Molecular Purgatory?". Molecular Cell. 22 (6): 713–717. doi:10.1016/j.molcel.2006.06.003. PMID 16793541.
  6. ↑ Olzmann, James A.; Richter, Caleb M.; Kopito, Ron R. (2013-01-22). "Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover". Proceedings of the National Academy of Sciences. 110 (4): 1345–1350. Bibcode:2013PNAS..110.1345O. doi:10.1073/pnas.1213738110. ISSN 0027-8424. PMC 3557085. PMID 23297223.
  7. ↑ Lee, Joon No; Kim, Hyeonwoo; Yao, Hongbing; Chen, Yan; Weng, Kayson; Ye, Jin (2010-12-14). "Identification of Ubxd8 protein as a sensor for unsaturated fatty acids and regulator of triglyceride synthesis". Proceedings of the National Academy of Sciences. 107 (50): 21424–21429. Bibcode:2010PNAS..10721424L. doi:10.1073/pnas.1011859107. ISSN 0027-8424. PMC 3003070. PMID 21115839.
  8. ↑ Zheng, Jing; Cao, Yu; Yang, Jun; Jiang, Hui (2022-10-06). "UBXD8 mediates mitochondria‐associated degradation to restrain apoptosis and mitophagy". EMBO Reports. 23 (10): e54859. doi:10.15252/embr.202254859. ISSN 1469-221X. PMC 9535754. PMID 35979733.
  9. ↑ Ye, Jin (October 2012). "Cellular responses to unsaturated fatty acids mediated by their sensor Ubxd8". Frontiers in Biology. 7 (5): 397–403. doi:10.1007/s11515-012-1247-6. ISSN 1674-7984. S2CID 15917436.
  10. ↑ Loregger, Anke; Raaben, Matthijs; Tan, Josephine; Scheij, Saskia; Moeton, Martina; van den Berg, Marlene; Gelberg-Etel, Hila; Stickel, Elmer; Roitelman, Joseph; Brummelkamp, Thijn; Zelcer, Noam (November 2017). "Haploid Mammalian Genetic Screen Identifies UBXD8 as a Key Determinant of HMGCR Degradation and Cholesterol Biosynthesis". Arteriosclerosis, Thrombosis, and Vascular Biology. 37 (11): 2064–2074. doi:10.1161/ATVBAHA.117.310002. ISSN 1079-5642. PMC 5671778. PMID 28882874.
  11. ↑ Kim, Hyeonwoo; Zhang, Hong; Meng, David; Russell, Geoffrey; Lee, Joon No; Ye, Jin (August 2013). "UAS domain of Ubxd8 and FAF1 polymerizes upon interaction with long-chain unsaturated fatty acids". Journal of Lipid Research. 54 (8): 2144–2152. doi:10.1194/jlr.M037218. PMC 3708364. PMID 23720822.
  12. ↑ Lee, Joon No; Kim, Hyeonwoo; Yao, Hongbing; Chen, Yan; Weng, Kayson; Ye, Jin (2010-12-14). "Identification of Ubxd8 protein as a sensor for unsaturated fatty acids and regulator of triglyceride synthesis". Proceedings of the National Academy of Sciences. 107 (50): 21424–21429. Bibcode:2010PNAS..10721424L. doi:10.1073/pnas.1011859107. ISSN 0027-8424. PMC 3003070. PMID 21115839.
  13. ↑ Lee, Joon No; Zhang, Xiangyu; Feramisco, Jamison D.; Gong, Yi; Ye, Jin (November 2008). "Unsaturated Fatty Acids Inhibit Proteasomal Degradation of Insig-1 at a Postubiquitination Step". Journal of Biological Chemistry. 283 (48): 33772–33783. doi:10.1074/jbc.M806108200. PMC 2586246. PMID 18835813.
  14. ↑ Ishiyama, Junichi; Taguchi, Ryoko; Akasaka, Yunike; Shibata, Saiko; Ito, Minoru; Nagasawa, Michiaki; Murakami, Koji (February 2011). "Unsaturated FAs prevent palmitate-induced LOX-1 induction via inhibition of ER stress in macrophages". Journal of Lipid Research. 52 (2): 299–307. doi:10.1194/jlr.M007104. PMC 3023550. PMID 21078775.
  15. ↑ Zhao, Linlin; Wang, Shuqing; Zhu, Qianli; Wu, Bin; Liu, Zhijun; OuYang, Bo; Chou, James J. (September 2017). "Specific Interaction of the Human Mitochondrial Uncoupling Protein 1 with Free Long-Chain Fatty Acid". Structure. 25 (9): 1371–1379.e3. doi:10.1016/j.str.2017.07.005. PMID 28781081.
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