真菌中的脂质不对称调节和P4型ATP酶

摘要/Abstract

摘要： 脂质组分在双分子膜中不对称分布是广泛存在于真核细胞中的现象,有助于膜系统的出芽和融合,从而促进胞吞胞吐、蛋白分选运输等生理过程。多种蛋白参与维持脂质不对称,其中P4型ATP酶是重要的脂质转运体。P4型ATP酶又称脂质翻转酶,主要介导氨基磷脂的转位。在酿酒酵母、新生隐球菌、白念珠菌和构巢曲霉中,多种P4型ATP酶亚基的缺失导致蛋白运输失常,对唑类药物的敏感性升高,细胞壁完整性受损,毒力减低,在巨噬细胞中生存能力减弱等表型,提示脂质翻转酶的重要性及其作为抗真菌靶点的潜力。

关键词: 脂质不对称, P4型ATP酶, 脂质翻转酶, Cdc50, 真菌, 酿酒酵母, 新生隐球菌

中图分类号:

R379

陈柯志, 刘锦燕, 王鲁灵, 项明洁. 真菌中的脂质不对称调节和P4型ATP酶[J]. 中国真菌学杂志, 2023, 18(4): 364-369.

参考文献

[1] KOBAYASHI T, MENON A K. Transbilayer lipid asymmetry[J]. Curr Biol, 2018, 28(8): R386-R391.
[2] VAN MEER G, VOELKER D R, FEIGENSON G W. Membrane lipids: where they are and how they behave[J]. Nat Rev Mol Cell Biol, 2008, 9(2): 112-124.
[3] MUTHUSAMY B P, NATARAJAN P, ZHOU X, et al. Linking phospholipid flippases to vesicle-mediated protein transport[J]. Biochim Biophys Acta, 2009, 1791(7): 612-619.
[4] TIMCENKO M, LYONS J A, JANULIENE D, et al. Structure and autoregulation of a P4-ATPase lipid flippase[J]. Nature, 2019, 571(7765): 366-370.
[5] VAN DER MARK V A, ELFERINK R P, PAULUSMA C C. P4 ATPases: flippases in health and disease[J]. Int J Mol Sci, 2013, 14(4): 7897-7922.
[6] GUINEA J. Global trends in the distribution of Candida species causing candidemia[J]. Clin Microbiol Infect, 2014, 20(Suppl 6): 5-10.
[7] ANDES D R, SAFDAR N, BADDLEY J W, et al. The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET)[J]. Transpl Infect Dis, 2016, 18(6): 921-931.
[8] FULLER J, DINGLE T C, BULL A, et al. Species distribution and antifungal susceptibility of invasive Candida isolates from Canadian hospitals: results of the CANWARD 2011-16 study[J]. J Antimicrob Chemother, 2019, 74(Suppl 4): iv48-iv54.
[9] 葛一平, 刘维达. 新生隐球菌荚膜多糖葡萄糖醛酸木糖甘露聚糖的意义[J]. 国际皮肤性病学杂志, 2008, 34(5): 336-338.
[10] DAL COL J, LAMBERTI M J, NIGRO A, et al. Phospholipid scramblase 1: a protein with multiple functions via multiple molecular interactors[J]. Cell Commun Signal, 2022, 20(1): 78.
[11] HIRAIZUMI M, YAMASHITA K, NISHIZAWA T, et al. Cryo-EM structures capture the transport cycle of the P4-ATPase flippase[J]. Science, 2019, 365(6458): 1149-1155.
[12] RIZZO J, STANCHEV L D, DA SILVA V K A, et al. Role of lipid transporters in fungal physiology and pathogenicity[J]. Comput Struct Biotechnol J, 2019, 17: 1278-1289.DOI: 10.1016/j.csbj.2019.09.001.
[13] BHATTACHARYA S, SAE-TIA S, FRIES B C. Candidiasis and mechanisms of antifungal resistance[J]. Antibiotics (Basel), 2020, 9(6):312.
[14] HASSAN Y, CHEW S Y, THAN L T L. Candida glabrata: pathogenicity and resistance mechanisms for adaptation and survival[J]. J Fungi (Basel), 2021, 7(8):667.
[15] GULSHAN K, MOYE-ROWLEY W S. Vacuolar import of phosphatidylcholine requires the ATP-binding cassette transporter Ybt1[J]. Traffic, 2011, 12(9): 1257-1268.
[16] SASSER T L, PADOLINA M, FRATTI R A. The yeast vacuolar ABC transporter Ybt1p regulates membrane fusion through Ca²⁺ transport modulation[J]. Biochem J, 2012, 448(3): 365-372.
[17] RIPMASTER T L, VAUGHN G P, WOOLFORD J L Jr.. DRS1 to DRS7, novel genes required for ribosome assembly and function in Saccharomyces cerevisiae[J]. Mol Cell Biol, 1993, 13(12): 7901-7912.
[18] CHEN C Y, INGRAM M F, ROSAL P H, et al. Role for Drs2p, a P-type ATPase and potential aminophospholipid translocase, in yeast late Golgi function[J]. J Cell Biol, 1999, 147(6): 1223-1236.
[19] MISU K, FUJIMURA-KAMADA K, UEDA T, et al. Cdc50p, a conserved endosomal membrane protein, controls polarized growth in Saccharomyces cerevisiae[J]. Mol Biol Cell, 2003, 14(2): 730-747.
[20] SAITO K, FUJIMURA-KAMADA K, FURUTA N, et al. Cdc50p, a protein required for polarized growth, associates with the Drs2p P-type ATPase implicated in phospholipid translocation in Saccharomyces cerevisiae[J]. Mol Biol Cell, 2004, 15(7): 3418-3432.
[21] GALL W E, GEETHING N C, HUA Z, et al. Drs2p-dependent formation of exocytic clathrin-coated vesicles in vivo[J]. Curr Biol, 2002, 12(18): 1623-1627.
[22] HANKINS H M, SERE Y Y, DIAB N S, et al. Phosphatidylserine translocation at the yeast trans-Golgi network regulates protein sorting into exocytic vesicles[J]. Mol Biol Cell, 2015, 26(25): 4674-4685.
[23] HUA Z, FATHEDDIN P, GRAHAM T R. An essential subfamily of Drs2p-related P-type ATPases is required for protein trafficking between Golgi complex and endosomal/vacuolar system[J]. Mol Biol Cell, 2002, 13(9): 3162-3177.
[24] KISHIMOTO T, MIOKA T, ITOH E, et al. Phospholipid flippases and Sfk1 are essential for the retention of ergosterol in the plasma membrane[J]. Mol Biol Cell, 2021, 32(15): 1374-1392.
[25] TAKAR M, WU Y, GRAHAM T R. The essential Neo1 protein from budding yeast plays a role in establishing aminophospholipid asymmetry of the plasma membrane[J]. J Biol Chem, 2016, 291(30): 15727-1539.
[26] DAS A, SLAUGHTER B D, UNRUH J R, et al. Flippase-mediated phospholipid asymmetry promotes fast Cdc42 recycling in dynamic maintenance of cell polarity[J]. Nat Cell Biol, 2012, 14(3): 304-310.
[27] ZHOU X, SEBASTIAN T T, GRAHAM T R. Auto-inhibition of Drs2p, a yeast phospholipid flippase, by its carboxyl-terminal tail[J]. J Biol Chem, 2013, 288(44): 31807-31815.
[28] YANG C, BIAN Z, BLECHERT O, et al. High prevalence of HIV-related cryptococcosis and increased resistance to fluconazole of the Cryptococcus neoformans complex in Jiangxi Province, South Central China[J]. Front Cell Infect Microbiol, 2021, 11: 723251.DOI: 10.3389/fcimb.2021.723251.
[29] MAZIARZ E K, PERFECT J R. Cryptococcosis[J]. Infect Dis Clin North Am, 2016, 30(1): 179-206.
[30] HUANG W, LIAO G, BAKER G M, et al. Lipid flippase subunit Cdc50 mediates drug resistance and virulence in Cryptococcus neoformans[J]. mBio,2016, 7(3):e00478-16.
[31] HU G, KRONSTAD J W. A putative P-type ATPase, Apt1, is involved in stress tolerance and virulence in Cryptococcus neoformans[J]. Eukaryot Cell, 2010, 9(1): 74-83.
[32] RIZZO J, COLOMBO A C, ZAMITH-MIRANDA D, et al. The putative flippase Apt1 is required for intracellular membrane architecture and biosynthesis of polysaccharide and lipids in Cryptococcus neoformans[J]. Biochim Biophys Acta Mol Cell Res, 2018, 1865(3): 532-541.
[33] HU G, CAZA M, BAKKEREN E, et al. A P4-ATPase subunit of the Cdc50 family plays a role in iron acquisition and virulence in Cryptococcus neoformans[J]. Cell Microbiol, 2017, 19(6).DOI: 10.1111/cmi.12718.
[34] CAO C, WANG Y, HUSAIN S, et al. A mechanosensitive channel governs lipid flippase-mediated echinocandin resistance in Cryptococcus neoformans[J]. mBio, 2019, 10(6):e01952-19.
[35] YU S J, CHANG Y L, CHEN Y L. Calcineurin signaling: lessons from Candida species[J]. FEMS Yeast Res, 2015, 15(4): fov016.
[36] TANCER R J, WANG Y, PAWAR S, et al. Development of antifungal peptides against Cryptococcus neoformans; leveraging knowledge about the cdc50Δ mutant susceptibility for lead compound development[J]. Microbiol Spectr, 2022, 10(2): e0043922.
[37] STANISZEWSKA M. Virulence factors in Candida species[J]. Curr Protein Pept Sci, 2020, 21(3): 313-323.
[38] XU D, ZHANG X, ZHANG B, et al. The lipid flippase subunit Cdc50 is required for antifungal drug resistance, endocytosis, hyphal development and virulence in Candida albicans[J]. FEMS Yeast Res, 2019, 19(3):foz033.
[39] FESTA R A, HELSEL M E, FRANZ K J, et al. Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection[J]. Chem Biol, 2014, 21(8): 977-987.
[40] 许海涛. 白念珠菌CaLEM3基因的功能研究[D].合肥市:淮北师范大学, 2021.
[41] SCHULTZHAUS Z, ZHENG W, WANG Z, et al. Phospholipid flippases DnfA and DnfB exhibit differential dynamics within the A. nidulans Spitzenkörper[J]. Fungal Genet Biol, 2017, 99: 26-28.DOI: 10.1016/j.fgb.2016.12.007.
[42] SCHULTZHAUS Z, YAN H, SHAW B D. Aspergillus nidulans flippase DnfA is cargo of the endocytic collar and plays complementary roles in growth and phosphatidylserine asymmetry with another flippase, DnfB[J]. Mol Microbiol, 2015, 97(1): 18-32.
[43] SCHULTZHAUS Z, CUNNINGHAM G A, MOURIÑO-PÉREZ R R, et al. The phospholipid flippase DnfD localizes to late Golgi and is involved in asexual differentiation in Aspergillus nidulans[J]. Mycologia, 2019, 111(1): 13-25.