UBXD8

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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]

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In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, from 4 to 28. Fatty acids are a major component of the lipids in some species such as microalgae but in some other organisms are not found in their standalone form, but instead exist as three main classes of esters: triglycerides, phospholipids, and cholesteryl esters. In any of these forms, fatty acids are both important dietary sources of fuel for animals and important structural components for cells.

<span class="mw-page-title-main">Lipid</span> Substance of biological origin that is soluble in nonpolar solvents

Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing energy, signaling, and acting as structural components of cell membranes. Lipids have applications in the cosmetic and food industries, and in nanotechnology.

<span class="mw-page-title-main">Lipolysis</span> Metabolism involving breakdown of lipids

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include leptin, glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

<span class="mw-page-title-main">4-Hydroxynonenal</span> Chemical compound

4-Hydroxynonenal, or 4-hydroxy-2E-nonenal or 4-hydroxy-2-nonenal or 4-HNE or HNE,, is an α,β-unsaturated hydroxyalkenal that is produced by lipid peroxidation in cells. 4-HNE is the primary α,β-unsaturated hydroxyalkenal formed in this process. It is a colorless oil. It is found throughout animal tissues, and in higher quantities during oxidative stress due to the increase in the lipid peroxidation chain reaction, due to the increase in stress events. 4-HNE has been hypothesized to play a key role in cell signal transduction, in a variety of pathways from cell cycle events to cellular adhesion.

Mycolic acids are long fatty acids found in the cell walls of Mycobacteriales taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis. They form the major component of the cell wall of many Mycobacteriales species. Despite their name, mycolic acids have no biological link to fungi; the name arises from the filamentous appearance their presence gives Mycobacteriales under high magnification. The presence of mycolic acids in the cell wall also gives Mycobacteriales a distinct gross morphological trait known as "cording". Mycolic acids were first isolated by Stodola et al. in 1938 from an extract of M. tuberculosis.

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<span class="mw-page-title-main">Sterol regulatory element-binding protein</span> Protein family

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

<span class="mw-page-title-main">SREBP cleavage-activating protein</span> Protein-coding gene in the species Homo sapiens

Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP, is a protein that in humans is encoded by the SCAP gene.

<span class="mw-page-title-main">Stearoyl-CoA 9-desaturase</span> Class of enzymes

Stearoyl-CoA desaturase (Δ-9-desaturase) is an endoplasmic reticulum enzyme that catalyzes the rate-limiting step in the formation of monounsaturated fatty acids (MUFAs), specifically oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA. Oleate and palmitoleate are major components of membrane phospholipids, cholesterol esters and alkyl-diacylglycerol. In humans, the enzyme is encoded by the SCD gene.

<span class="mw-page-title-main">Valosin-containing protein</span> Protein-coding gene in the species Homo sapiens

Valosin-containing protein (VCP) or transitional endoplasmic reticulum ATPase also known as p97 in mammals and CDC48 in S. cerevisiae, is an enzyme that in humans is encoded by the VCP gene. The TER ATPase is an ATPase enzyme present in all eukaryotes and archaebacteria. Its main function is to segregate protein molecules from large cellular structures such as protein assemblies, organelle membranes and chromatin, and thus facilitate the degradation of released polypeptides by the multi-subunit protease proteasome.

<span class="mw-page-title-main">AMFR</span> Protein-coding gene in the species Homo sapiens

Autocrine motility factor receptor, isoform 2 is a protein that in humans is encoded by the AMFR gene.

<span class="mw-page-title-main">Perilipin-2</span> Protein-coding gene in the species Homo sapiens

Adipose differentiation-related protein, also known as perilipin 2, ADRP or adipophilin, is a protein which belongs to the perilipin (PAT) family of cytoplasmic lipid droplet (CLD)–binding proteins. In humans it is encoded by the ADFP gene. This protein surrounds the lipid droplet along with phospholipids and is involved in assisting the storage of neutral lipids within the lipid droplets.

<span class="mw-page-title-main">Adipose triglyceride lipase</span> Mammalian protein found in Homo sapiens

Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.

Lipid droplets, also referred to as lipid bodies, oil bodies or adiposomes, are lipid-rich cellular organelles that regulate the storage and hydrolysis of neutral lipids and are found largely in the adipose tissue. They also serve as a reservoir for cholesterol and acyl-glycerols for membrane formation and maintenance. Lipid droplets are found in all eukaryotic organisms and store a large portion of lipids in mammalian adipocytes. Initially, these lipid droplets were considered to merely serve as fat depots, but since the discovery in the 1990s of proteins in the lipid droplet coat that regulate lipid droplet dynamics and lipid metabolism, lipid droplets are seen as highly dynamic organelles that play a very important role in the regulation of intracellular lipid storage and lipid metabolism. The role of lipid droplets outside of lipid and cholesterol storage has recently begun to be elucidated and includes a close association to inflammatory responses through the synthesis and metabolism of eicosanoids and to metabolic disorders such as obesity, cancer, and atherosclerosis. In non-adipocytes, lipid droplets are known to play a role in protection from lipotoxicity by storage of fatty acids in the form of neutral triacylglycerol, which consists of three fatty acids bound to glycerol. Alternatively, fatty acids can be converted to lipid intermediates like diacylglycerol (DAG), ceramides and fatty acyl-CoAs. These lipid intermediates can impair insulin signaling, which is referred to as lipid-induced insulin resistance and lipotoxicity. Lipid droplets also serve as platforms for protein binding and degradation. Finally, lipid droplets are known to be exploited by pathogens such as the hepatitis C virus, the dengue virus and Chlamydia trachomatis among others.

<span class="mw-page-title-main">Diglyceride</span> Type of fat derived from glycerol and two fatty acids

A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. Diglycerides are natural components of food fats, though minor in comparison to triglycerides. DAGs can act as surfactants and are commonly used as emulsifiers in processed foods. DAG-enriched oil has been investigated extensively as a fat substitute due to its ability to suppress the accumulation of body fat; with total annual sales of approximately USD 200 million in Japan since its introduction in the late 1990s till 2009.

<span class="mw-page-title-main">UBX protein domain</span> Protein domain

In molecular biology, the UBX protein domain is found in ubiquitin-regulatory proteins, which are members of the ubiquitination pathway, as well as a number of other ubiquitin-like proteins including FAF-1, the human Rep-8 reproduction protein and several hypothetical proteins from yeast. The function of the UBX domain is not known although the fragment of avian FAF-1 containing the UBX domain causes apoptosis of transfected cells.

<span class="mw-page-title-main">Discovery and development of gastrointestinal lipase inhibitors</span>

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<span class="mw-page-title-main">Fas associated factor family member 2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Perilipin-5</span> Mammalian protein found in Homo sapiens

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Hypoxia inducible lipid droplet-associated is a protein that in humans is encoded by the HILPDA gene.

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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