Inhibition of retroviral Gag assembly by non-silencing miRNAs promotes autophagic viral degradation

doi:10.1007/s13238-017-0461-z

Protein Cell

2018, Vol. 9

Issue (7) : 640-651 https://doi.org/10.1007/s13238-017-0461-z

RESEARCH ARTICLE

Inhibition of retroviral Gag assembly by non-silencing miRNAs promotes autophagic viral degradation

Na Qu¹, Zhao Ma¹, Mengrao Zhang¹, Muaz N. Rushdi^1,², Christopher J. Krueger^1,², Antony K. Chen¹(

)

¹. Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China
². Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA

Download: PDF(2376 KB)
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

We recently reported an unconventional mechanism by which miRNAs inhibit HIV-1 viral production. This occurs when miRNAs bind nonspecifically to the viral structural protein Gag, interfering with viral RNA-mediated Gag assembly at the plasma membrane. Consequently, misassembled viral complexes are redirected into the endocytic pathway where they are delivered to lysosomes for degradation. In this study, we demonstrate that autophagy is a critical mediator of the viral degradation pathway and that this pathway is not HIV-1 specific. Misassembled viral complexes were found to colocalize extensively with LC3 and p62 in late endosomes/lysosomes, demonstrating a convergence of autophagy with functional degradative compartments. Knocking down autophagosome formation machineries reduced this convergence, while treatment with autophagy-inducer rapamycin enhanced the convergence. Furthermore, similar autophagy-dependent nonspecific miRNA inhibition of murine leukemia virus (MLV) assembly was shown. Overall, these results reveal autophagy as a crucial regulator of the retroviral degradation pathway in host cells initiated by nonspecific miRNA-Gag interactions. These findings could have significant implications for understanding how cells may regulate retroviral complex assembly by miRNA expression and autophagy, and raise the possibility that similar regulations can occur in other biological contexts.

Keywords microRNA Gag protein autophagy

Corresponding Author(s): Antony K. Chen

Issue Date: 11 July 2018

Cite this article:

Na Qu,Zhao Ma,Mengrao Zhang, et al. Inhibition of retroviral Gag assembly by non-silencing miRNAs promotes autophagic viral degradation[J]. Protein Cell, 2018, 9(7): 640-651.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-017-0461-z
https://academic.hep.com.cn/pac/EN/Y2018/V9/I7/640

1	Aldovini A, Young RA (1990) Mutations of RNA and protein sequences involved in human immunodeficiency virus type 1 packaging result in production of noninfectious virus. J Virol 64:1920–1926
2	Berkowitz RD, Luban J, Goff SP (1993) Specific binding of human immunodeficiency virus type 1 gag polyprotein and nucleocapsid protein to viral RNAs detected by RNA mobility shift assays. J Virol 67:7190–7200
3	Briggs JA, Simon MN, Gross I, Krausslich HG, Fuller SD, Vogt VM, Johnson MC (2004) The stoichiometry of Gag protein in HIV-1. Nat Struct Mol Biol 11:672–675 https://doi.org/10.1038/nsmb785
4	Campbell S, Vogt VM (1995) Self-assembly in vitro of purified CANC proteins from Rous sarcoma virus and human immunodeficiency virus type 1. J Virol 69:6487–6497
5	Chen AK, Sengupta P, Waki K, Van Engelenburg SB, Ochiya T, Ablan SD, Freed EO, Lippincott-Schwartz J (2014) MicroRNA binding to the HIV-1 Gag protein inhibits Gag assembly and virus production. Proc Natl Acad Sci USA 111:E2676–E2683 https://doi.org/10.1073/pnas.1408037111
6	Eiring AM, Harb JG, Neviani P, Garton C, Oaks JJ, Spizzo R, Liu S, Schwind S, Santhanam R, Hickey CJet al. (2010) miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell 140:652–665 https://doi.org/10.1016/j.cell.2010.01.007
7	Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJet al. (2012) MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci USA 109:E2110–E2116 https://doi.org/10.1073/pnas.1209414109
8	Feng Y, He D, Yao Z, Klionsky DJ (2014) The machinery of macroautophagy. Cell Res 24:24–41 https://doi.org/10.1038/cr.2013.168
9	Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114 https://doi.org/10.1038/nrg2290
10	Frankel LB, Lubas M, Lund AH (2017) Emerging connections between RNA and autophagy. Autophagy 13:3–23 https://doi.org/10.1080/15548627.2016.1222992
11	Gorelick RJ, Nigida SM Jr, Bess JW Jr, Arthur LO, Henderson LE, Rein A (1990) Noninfectious human immunodeficiency virus type 1 mutants deficient in genomic RNA. J Virol 64:3207–3211
12	Jin J, Sherer NM, Heidecker G, Derse D, Mothes W (2009) Assembly of the murine leukemia virus is directed towards sites of cell-cell contact. Plos Biol 7:e1000163 https://doi.org/10.1371/journal.pbio.1000163
13	Jouvenet N, Neil SJD, Bess C, Johnson MC, Virgen CA, Simon SM, Bieniasz PD (2006) Plasma membrane is the site of productive HIV-1 particle assembly. Plos Biol 4:2296–2310 https://doi.org/10.1371/journal.pbio.0040435
14	Jouvenet N, Simon SM, Bieniasz PD (2009) Imaging the interaction of HIV-1 genomes and Gag during assembly of individual viral particles. Proc Natl Acad Sci USA 106:19114–19119 https://doi.org/10.1073/pnas.0907364106
15	Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8:931–937 https://doi.org/10.1038/nrm2245
16	Kutluay SB, Bieniasz PD (2010) Analysis of the initiating events in HIV-1 particle assembly and genome packaging. PLoS Pathog 6: e1001200 https://doi.org/10.1371/journal.ppat.1001200
17	Kutluay SB, Zang T, Blanco-Melo D, Powell C, Jannain D, Errando M, Bieniasz PD (2014) Global changes in the RNA binding specificity of HIV-1 gag regulate virion genesis. Cell 159:1096–1109 https://doi.org/10.1016/j.cell.2014.09.057
18	Lehmann SM, Kruger C, Park B, Derkow K, Rosenberger K, Baumgart J, Trimbuch T, Eom G, Hinz M, Kaul Det al. (2012) An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15:827–835 https://doi.org/10.1038/nn.3113
19	Linial ML (1999) Foamy viruses are unconventional retroviruses. J Virol 73:1747–1755
20	Liu K, Czaja MJ (2013) Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ 20:3–11 https://doi.org/10.1038/cdd.2012.63
21	Mizushima N (2007) Autophagy: process and function. Gene Dev 21:2861–2873 https://doi.org/10.1101/gad.1599207
22	Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075 https://doi.org/10.1038/nature06639
23	Mullers E (2013) The foamy virus Gag proteins: what makes them different? Viruses-Basel 5:1023–1041 https://doi.org/10.3390/v5041023
24	Muriaux D, Mirro J, Harvin D, Rein A (2001) RNA is a structural element in retrovirus particles. Proc Natl Acad Sci USA 98:5246–5251 https://doi.org/10.1073/pnas.091000398
25	Muriaux D, Costes S, Nagashima K, Mirro J, Cho E, Lockett S, Rein A (2004) Role of murine leukemia virus nucleocapsid protein in virus assembly. J Virol 78:12378–12385 https://doi.org/10.1128/JVI.78.22.12378-12385.2004
26	Ono A, Waheed AA, Joshi A, Freed EO (2005) Association of human immunodeficiency virus type 1 gag with membrane does not require highly basic sequences in the nucleocapsid: use of a novel gag multimerization assay. J Virol 79:14131–14140 https://doi.org/10.1128/JVI.79.22.14131-14140.2005
27	Prud’homme GJ, Glinka Y, Lichner Z, Yousef GM (2016) Neuropilin-1 is a receptor for extracellular miRNA and AGO2/miRNA complexes and mediates the internalization of miRNAs that modulate cell function. Oncotarget 7:68057–68071 https://doi.org/10.18632/oncotarget.10929
28	Rambold AS, Lippincott-Schwartz J (2011) Mechanisms of mitochondriaand autophagy crosstalk. Cell Cycle 10:4032–4038 https://doi.org/10.4161/cc.10.23.18384
29	Ranganathan P, Ngankeu A, Zitzer NC, Leoncini P, Yu XY, Casadei L, Challagundla K, Reichenbach DK, Garman S, Ruppert ASet al. (2017) Serum miR-29a is upregulated in acute graft-versus-host disease and activates dendritic cells through TLR binding. J Immunol 198:2500–2512 https://doi.org/10.4049/jimmunol.1601778
30	Rein A, Harvin DP, Mirro J, Ernst SM, Gorelick RJ (1994) Evidence that a central domain of nucleocapsid protein is required for RNA packaging in murine leukemia-virus. J Virol 68:6124–6129
31	Rulli SJ Jr, Hibbert CS, Mirro J, Pederson T, Biswal S, Rein A (2007) Selective and nonselective packaging of cellular RNAs in retrovirus particles. J Virol 81:6623–6631 https://doi.org/10.1128/JVI.02833-06
32	Sanchez-Wandelmer J, Reggiori F (2013) Amphisomes: out of the autophagosome shadow? EMBO J 32:3116–3118 https://doi.org/10.1038/emboj.2013.246
33	Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid Bet al. (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682 https://doi.org/10.1038/nmeth.2019
34	Sharp PA (2009) The centrality of RNA. Cell 136:577–580 https://doi.org/10.1016/j.cell.2009.02.007
35	Shaw KL, Lindemann D, Mulligan MJ, Goepfert PA (2003) Foamy virus envelope glycoprotein is sufficient for particle budding and release. J Virol 77:2338–2348 https://doi.org/10.1128/JVI.77.4.2338-2348.2003
36	Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13:423–433 https://doi.org/10.1038/ncb2210
37	Wong E, Bejarano E, Rakshit M, Lee K, Hanson HH, Zaarur N, Phillips GR, Sherman MY, Cuervo AM (2012) Molecular determinants of selective clearance of protein inclusions by autophagy. Nat Commun 3:1240 https://doi.org/10.1038/ncomms2244
38	Yelamanchili SV, Lamberty BG, Rennard DA, Morsey BM, Hochfelder CG, Meays BM, Levy E, Fox HS (2015) MiR-21 in extracellular vesicles leads to neurotoxicity via TLR7 signaling in SIV neurological disease. PLoS Pathog 11:e1005032 https://doi.org/10.1371/journal.ppat.1005032
39	Zhao D, Yang Y, Qu N, Chen M, Ma Z, Krueger CJ, Behlke MA, Chen AK (2016) Single-molecule detection and tracking of RNA transcripts in living cells using phosphorothioate-optimized 2’-Omethyl RNA molecular beacons. Biomaterials 100:172–183 https://doi.org/10.1016/j.biomaterials.2016.05.022

[1]

PAC-0640-17213-CA_suppl_1

Download

[1]	Kun Liu, Jiani Cao, Xingxing Shi, Liang Wang, Tongbiao Zhao. Cellular metabolism and homeostasis in pluripotency regulation[J]. Protein Cell, 2020, 11(9): 630-640.
[2]	Xi Chen, Lin Wang, Rujin Huang, Hui Qiu, Peizhe Wang, Daren Wu, Yonglin Zhu, Jia Ming, Yangming Wang, Jianbin Wang, Jie Na. Dgcr8 deletion in the primitive heart uncovered novel microRNA regulating the balance of cardiac-vascular gene program[J]. Protein Cell, 2019, 10(5): 327-346.
[3]	Yuanyuan Gu, Shuoxin Liu, Xiaodan Zhang, Guimin Chen, Hongwei Liang, Mengchao Yu, Zhicong Liao, Yong Zhou, Chen-Yu Zhang, Tao Wang, Chen Wang, Junfeng Zhang, Xi Chen. Oncogenic miR-19a and miR-19b co-regulate tumor suppressor MTUS1 to promote cell proliferation and migration in lung cancer[J]. Protein Cell, 2017, 8(6): 455-466.
[4]	Shaohong Chen, Guangxia Gao. MicroRNAs recruit eIF4E2 to repress translation of target mRNAs[J]. Protein Cell, 2017, 8(10): 750-761.
[5]	Zhi-Dong Liu,Su Zhang,Jian-Jin Hao,Tao-Rong Xie,Jian-Sheng Kang. Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling[J]. Protein Cell, 2016, 7(9): 638-650.
[6]	Jiaxiang Shao,Xiao Yang,Tengyuan Liu,Tingting Zhang,Qian Reuben Xie,Weiliang Xia. Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage[J]. Protein Cell, 2016, 7(4): 281-290.
[7]	Zhiju Zhao,Shu Li,Erwei Song,Suling Liu. The roles of ncRNAs and histone-modifiers in regulating breast cancer stem cells[J]. Protein Cell, 2016, 7(2): 89-99.
[8]	Qian Fan,Xiangrui Meng,Hongwei Liang,Huilai Zhang,Xianming Liu,Lanfang Li,Wei Li,Wu Sun,Haiyang Zhang,Ke Zen,Chen-Yu Zhang,Zhen Zhou,Xi Chen,Yi Ba. miR-10a inhibits cell proliferation and promotes cell apoptosis by targeting BCL6 in diffuse large B-cell lymphoma[J]. Protein Cell, 2016, 7(12): 899-912.
[9]	Yanqing Liu,Uzair-ur-Rehman,Yu Guo,Hongwei Liang,Rongjie Cheng,Fei Yang,Yeting Hong,Chihao Zhao,Minghui Liu,Mengchao Yu,Xinyan Zhou,Kai Yin,Jiangning Chen,Junfeng Zhang,Chen-Yu Zhang,Feng Zhi,Xi Chen. miR-181b functions as an oncomiR in colorectal cancer by targeting PDCD4[J]. Protein Cell, 2016, 7(10): 722-734.
[10]	Yan-Cheng Tang,Hong-Xia Tian,Tao Yi,Hu-Biao Chen. The critical roles of mitophagy in cerebral ischemia[J]. Protein Cell, 2016, 7(10): 699-713.
[11]	Lin Lin,Qingqing Cai,Xiaoyan Zhang,Hongwei Zhang,Yang Zhong,Congjian Xu,Yanyun Li. Two less common human microRNAs miR-875 and miR-3144 target a conserved site of E6 oncogene in most high-risk human papillomavirus subtypes[J]. Protein Cell, 2015, 6(8): 575-588.
[12]	Wenzhi Feng,Tong Wu,Xiaoyu Dan,Yuling Chen,Lin Li,She Chen,Di Miao,Haiteng Deng,Xinqi Gong,Li Yu. Phosphorylation of Atg31 is required for autophagy[J]. Protein Cell, 2015, 6(4): 288-296.
[13]	Anna Gortat,Mónica Sancho,Laura Mondragón,Àgel Messeguer,Enrique Pérez-Payá,Mar Orzáez. Apaf1 inhibition promotes cell recovery from apoptosis[J]. Protein Cell, 2015, 6(11): 833-843.
[14]	Jianhua Xiong. Atg7 in development and disease: panacea or Pandora’s Box?[J]. Protein Cell, 2015, 6(10): 722-734.
[15]	Xiaojuan Chen,Kai Wang,Yaling Xing,Jian Tu,Xingxing Yang,Qian Zhao,Kui Li,Zhongbin Chen. Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity[J]. Protein Cell, 2014, 5(12): 912-927.

Viewed

Full text

Abstract

Cited

Shared

Discussed