Immiscible immunity

doi:10.1126/science.abe7891

GSTDTAP > 气候变化

DOI	10.1126/science.abe7891
	Immiscible immunity
	Douglas R. Green
	2020-10-16
发表期刊	Science
出版年	2020
英文摘要	Oil and water do not mix. This simple fact drives the formation of the lipid-based boundaries of cells, nuclei, and most organelles that make life possible. But a simpler structure, the lipid droplet (LD), coalesces in the cell cytoplasm and comprises a core of neutral fatty acids [mostly triacylglycerides (TAGs) and sterol esters] surrounded by polar lipids (phospholipids and sterols) and associated proteins. An LD is, in essence, a drop of oil, but it has properties that many proponents suggest give it organelle status. As a rich energy reserve, LDs fuel β-oxidation in m itochondria and often physically associate with these organelles. It follows, however, that invading microorganisms similarly exploit LDs as an energy source and, therefore, that cells might “arm” LDs with innate host defense mechanisms. On page 309 of this issue, Bosch et al. ([ 1 ][1]) explore the relations between the antimicrobial activities of LDs and their function as a fuel depot for mitochondria. ![Figure][2] Double duty Perilipin-5 (PLIN5) protein tethers lipid droplets (LDs) to mitochondria, and LDs provide fuel for β-oxidation (left). When the cells sense microbes, the LD proteome changes, and LDs grow in number and size. PLIN2 stabilizes LDs, and antimicrobial proteins increase (right). PLIN5 and thus β-oxidation decrease. GRAPHIC: A. KITTERMAN/ SCIENCE LDs were identified more than 130 years ago and reside in all cells and cell types ([ 2 ][3]). A century later, they received interest (and perhaps organelle status) with the discovery of perilipins (PLINs), proteins that function in the assembly and stability of LDs ([ 3 ][4]). A link to infection came with the discovery, by several authors of Bosch et al. , that microbial stimulation of macrophages in Drosophila induces formation of LDs with antimicrobial activity ([ 4 ][5]). This activity was dependent on a protein, Jabba, that recruits histones to LDs, and flies lacking Jabba displayed increased sensitivity to bacterial infection. Extranuclear histones in flies and mammals are known to have antimicrobial activity ([ 5 ][6]), but no Jabba homolog exists in mammals. Nevertheless, activation of cell-surface Toll-like receptors (TLRs), which are sensors of diverse microbial products, strongly stimulates TAG uptake, synthesis, and retention in human and mouse macrophages ([ 6 ][7]), suggesting a similar antimicrobial role for LDs in mammalian cells. Bosch et al. examined hepatocytes in mice injected with the TLR4 ligand lipo polysaccharide (LPS; a bacterial toxin) and observed an increase in LDs with heightened antimicrobial activity. They also observed similar effects in human monocyte-derived macrophages treated with LPS. Using a proteomic approach, the authors found that 30% of the LD-associated proteome changed (for the most part, increased) in response to LPS, including several PLIN proteins as well as proteins with known antiviral, antibacterial, and anti protozoan activity (see the figure). Coexpression analysis revealed that expression of several of the latter proteins correlated with that of PLIN2, the major protein involved in the stabilization of LDs ([ 7 ][8]). Among the antibacterial proteins in the PLIN2 cluster was cathelicidin (CAMP), a broadly active antimicrobial peptide with immune regulatory and chemotactic functions. Bosch et al. found that silencing CAMP expression in human macrophages prevented their antimicrobial response to intracellular Escherichia coli . CAMP is produced as a proprotein with an amino-terminal signal peptide that is cleaved before CAMP is secreted. However, the authors found that LD-associated CAMP retained the signal peptide, suggesting that the signal peptide of CAMP functions not only in secretion but also in targeting CAMP to LDs. By directly steering CAMP to LDs, the organelles acquired antimicrobial activity against E. coli, Listeria monocytogenes , and methicillin-resistant Staphylococcus aureus . LD-associated histones also increased in LPS-treated cells but appeared to play little to no role in antimicrobial effects of LDs. Ligation of cell surface TLRs on mouse and human macrophages reduces mitochondrial β-oxidation, an effect attributed to down-regulation of adipose triglyceride lipase (ATGL) expression ([ 6 ][7]), and LPS-treated macrophages shift to a Warburg effect–like oxidative glycolysis ([ 8 ][9]). However, whereas Bosch et al. similarly found that LPS treatment decreased mitochondrial β-oxidation, they did not report substantial change in ATGL expression upon LPS treatment of hepatocytes. They did observe reduced expression of PLIN5, the major protein responsible for tethering mitochondria to LD ([ 9 ][10]). Another protein suspected of mediating such tethering, diacylglycerol O -acyltransferase 2 ([ 10 ][11]), was found by others to be up-regulated in LPS-treated macrophages ([ 6 ][7]), but again, Bosch et al. did not find this effect in hepatocytes. Nevertheless, they observed that LPS treatment reduced contact between LDs and mitochondria, and enforced expression of PLIN5 in cell lines increased the numbers and lengths of such contacts and prevented their reduction by LPS. These results suggest that regulation of PLIN5 expression controls the fueling of mitochondria by LD for β-oxidation. Enforced expression of PLIN5 reduced the intracellular antimicrobial effects of LPS treatment in cell lines. This suggests that the uncoupling of mitochondria from LDs might be important for their antimicrobial effects. But why? Because LD-associated CAMP was the major factor mediating LPS-induced antibacterial activity, it might be that mitochondria compete with bacteria for LD binding or otherwise prevent the effects of CAMP on bacteria. Alternatively, the LPS-induced expression of CAMP (and perhaps other antimicrobial effectors) might depend on the LPS-induced metabolic shift to glycolysis. It would be useful to determine if enforced PLIN5 expression affects metabolism in LPS-treated cells and if this, in turn, affects expression of CAMP. Although LPS ligation of TLR4 directly stimulates LD formation in macrophages ([ 6 ][7]), this effect in vivo depends in large part on the action of platelet -activating factor (PAF) ([ 11 ][12]). To what extent the LPS-induced changes noted by Bosch et al. in 30% of the LD proteome might result from PAF or other LPS-induced cytokines remains unknown. Nevertheless, the ability of LPs and presumably other TLR agonists to increase intracellular innate defenses against infection in mammals and how this relates to the functions of LDs and their interactions with mitochondria open new avenues for exploration. There is great and justifiable excitement regarding the functions of LDs and other membraneless organelles and their associated phase transitions in many cellular processes. The studies by Bosch et al. suggest that we have much to learn about these drops of oil in cells. 1. [↵][13]1. M. Bosch et al ., Science 370, eaay8085 (2020). [OpenUrl][14][CrossRef][15] 2. [↵][16]1. R. V. Farese Jr., 2. T. C. Walther , Cell 139, 855 (2009). [OpenUrl][17][CrossRef][18][PubMed][19][Web of Science][20] 3. [↵][21]1. A. S. Greenberg et al ., J. Biol. Chem. 266, 11341 (1991). [OpenUrl][22][Abstract/FREE Full Text][23] 4. [↵][24]1. P. Anand et al ., eLife 1, e00003 (2012). [OpenUrl][25][CrossRef][26][PubMed][27] 5. [↵][28]1. M. Hoeksema, 2. M. van Eijk, 3. H. P. Haagsman, 4. K. L. Hartshorn , Future Microbiol. 11, 441 (2016). [OpenUrl][29][CrossRef][30] 6. [↵][31]1. Y. L. Huang et al ., J. Biol. Chem. 289, 3001 (2014). [OpenUrl][32][Abstract/FREE Full Text][33] 7. [↵][34]1. M. Fukushima et al ., In Vitro Cell. Dev. Biol. Anim. 41, 321 (2005). [OpenUrl][35][CrossRef][36][PubMed][37][Web of Science][38] 8. [↵][39]1. L. A. O'Neill, 2. E. J. Pearce , J. Exp. Med. 213, 15 (2016). [OpenUrl][40][Abstract/FREE Full Text][41] 9. [↵][42]1. H. Wang et al ., J. Lipid Res. 52, 2159 (2011). [OpenUrl][43][Abstract/FREE Full Text][44] 10. [↵][45]1. S. J. Stone et al ., J. Biol. Chem. 284, 5352 (2009). [OpenUrl][46][Abstract/FREE Full Text][47] 11. [↵][48]1. R. N. Gomes et al ., Shock 26, 41 (2006). [OpenUrl][49][PubMed][50][Web of Science][51] Acknowledgments: D.R.G. is supported by grants from the U.S. National Institutes of Health and by the ALSAC. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计	被引频次：5[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/299330
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Douglas R. Green. Immiscible immunity[J]. Science,2020.
APA	Douglas R. Green.(2020).Immiscible immunity.Science.
MLA	Douglas R. Green."Immiscible immunity".Science (2020).