Intracellular vesicle acidification promotes maturation of infectious poliovirus particles.
Intracellular vesicle acidification promotes maturation of infectious poliovirus particles.
复制标题
DOI：
10.1371/journal.ppat.1003046
复制
发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Jackson WT
中科院分区：
文献类型：
--
作者：
Richards AL;Jackson WT
自噬途径作为针对多种病原体的免疫应答的一部分起作用。然而，一些病原体破坏自噬信号以促进自身复制。在许多情况下，已经证明这些病原体抑制或延迟自噬的降解方面。在这里，使用脊髓灰质炎病毒作为模型病毒，我们第一次报告了真正的自噬降解发生在感染病毒的复制是由自噬促进。我们发现这种降解并不是促进脊髓灰质炎病毒复制所必需的。然而，在自噬的情况下，囊泡酸化先于将货物递送到溶酶体，这是正常水平的病毒产生所必需的。我们表明，阻断自噬体的形成抑制病毒RNA的合成和病毒周期中的后续步骤，而抑制囊泡酸化只抑制病毒颗粒的最终成熟裂解。我们认为，颗粒组装，基因组的组装，和病毒粒子的成熟可能发生在一个细胞室，我们建议酸性成熟的自噬体作为候选囊泡。我们讨论了我们的研究结果在理解脊髓灰质炎病毒复制的后期阶段，包括病毒体的形成和成熟以及感染性病毒从细胞中的排出的影响。自噬降解途径是众所周知的先天免疫因子。几种病原体，包括脊髓灰质炎病毒（PV），几种医学上重要的RNA病毒的模型，为了自己的利益破坏了这一途径。在这样做的过程中，病原体通常会抑制该途径的降解部分，可能是为了防止它们自身的破坏。令人惊讶的是，PV感染导致高水平的降解性自噬。然而，我们发现自噬降解是不稳定的PV复制。抑制自噬体的形成抑制病毒RNA复制和病毒产生中的后续步骤。在自噬体的情况下，抑制囊泡的酸化先于与溶酶体的融合和自噬降解，从而抑制病毒产生中的更晚的步骤。我们的数据表明，细胞的酸性区室在最后的成熟步骤中发挥重要作用，切割衣壳蛋白以产生感染性病毒。重要的是，这些数据也对长期存在的假设提出了质疑，即感染性脊髓灰质炎病毒产生的所有步骤都是胞质的。
The autophagic pathway acts as part of the immune response against a variety of pathogens. However, several pathogens subvert autophagic signaling to promote their own replication. In many cases it has been demonstrated that these pathogens inhibit or delay the degradative aspect of autophagy. Here, using poliovirus as a model virus, we report for the first time bona fide autophagic degradation occurring during infection with a virus whose replication is promoted by autophagy. We found that this degradation is not required to promote poliovirus replication. However, vesicular acidification, which in the case of autophagy precedes delivery of cargo to lysosomes, is required for normal levels of virus production. We show that blocking autophagosome formation inhibits viral RNA synthesis and subsequent steps in the virus cycle, while inhibiting vesicle acidification only inhibits the final maturation cleavage of virus particles. We suggest that particle assembly, genome encapsidation, and virion maturation may occur in a cellular compartment, and we propose the acidic mature autophagosome as a candidate vesicle. We discuss the implications of our findings in understanding the late stages of poliovirus replication, including the formation and maturation of virions and egress of infectious virus from cells. The autophagic degradation pathway is a well-known agent of innate immunity. Several pathogens, including poliovirus (PV), a model for several medically important RNA viruses, subvert this pathway for their own benefit. In doing so, pathogens often inhibit the degradative portion of the pathway, presumably to prevent their own destruction. We show here that, surprisingly, PV infection results in high levels of degradative autophagy. However, we find that autophagic degradation is dispensable for PV replication. Inhibiting the formation of autophagosomes inhibits virus RNA replication and subsequent steps in virus production. Inhibiting the acidification of vesicles, which in the case of autophagosomes precedes fusion with lysosomes and autophagic degradation, inhibits a much later step in virus production. Our data suggest an important role for an acidic compartment of the cell in the final maturation step, cleaving a capsid protein to generate infectious virus. Importantly, these data also call into question the long-standing hypothesis that all steps in the production of infectious poliovirus are cytosolic.
登录
查看更多内容
DOI：
10.1083/jcb.201106098
发表时间：
2011-12-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bruns C;McCaffery JM;Curwin AJ;Duran JM;Malhotra V
通讯作者：
Malhotra V
影响因子：
5.4
作者：
FERNANDEZTOMAS, CB;BALTIMORE, D
通讯作者：
BALTIMORE, D
影响因子：
3.4
作者：
Amer, AO;Swanson, MS
通讯作者：
Swanson, MS
影响因子：
30.3
作者：
Heaton NS;Randall G
通讯作者：
Randall G
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje