Hepatitis C virus infection increases autophagosome stability by suppressing lysosomal fusion through an Arl8b-dependent mechanism

Jones-Jamtgaard, Kellyann N.; Wozniak, Ann L.; Koga, Hiroshi; Ralston, Robert; Weinman, Steven A.

doi:10.1074/jbc.ra119.008229

Cited by 19 publications

(15 citation statements)

References 43 publications

(52 reference statements)

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“…However, there was no change in autophagolysosome formation in SARS-CoV-2 infected cells. Similar phenomenon is observed in the case of HCV infection (47). Lack of Lamp2 protein increased the level of viral RNA in the SARS-CoV-2 infected cells.…”

Section: Discussionsupporting

confidence: 84%

RNA-protein interaction analysis of SARS-CoV-2 5’- and 3’-untranslated regions identifies an antiviral role of lysosome-associated membrane protein-2

Verma

Saha

Kumar

et al. 2021

Preprint

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Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is a positive-strand RNA virus. Viral genome is capped at the 5’-end, followed by an untranslated region (UTR). There is poly-A tail at 3’-end, preceded by an UTR. Self-interaction between the RNA regulatory elements present within 5’- and 3’-UTRs as well as their interaction with host/virus-encoded proteins mediate the function of 5’- and 3’-UTRs. Using RNA-protein interaction detection (RaPID) assay coupled to liquid chromatography with tandem mass-spectrometry, we identified host interaction partners of SARS-CoV-2 5’- and 3’-UTRs and generated an RNA-protein interaction network. By combining these data with the previously known protein-protein interaction data proposed to be involved in virus replication, we generated the RNA-protein-protein interaction (RPPI) network, likely to be essential for controlling SARS-CoV-2 replication. Notably, bioinformatics analysis of the RPPI network revealed the enrichment of factors involved in translation initiation and RNA metabolism. Lysosome-associated membrane protein-2a (Lamp2a) was one of the host proteins that interact with the 5’-UTR. Further studies showed that Lamp2 level is upregulated in SARS-CoV-2 infected cells and overexpression of Lamp2a and Lamp2b variants reduced viral RNA level in infected cells and vice versa. In summary, our study provides an useful resource of SARS-CoV-2 5’- and 3’-UTR binding proteins and reveal the antiviral function of host Lamp2 protein.ImportanceReplication of a positive-strand RNA virus involves an RNA-protein complex consisting of viral genomic RNA, host RNA(s), virus-encoded proteins and host proteins. Dissecting out individual components of the replication complex will help decode the mechanism of viral replication. 5’- and 3’-UTRs in positive-strand RNA viruses play essential regulatory roles in virus replication. Here, we identified the host proteins that associate with the UTRs of SARS-CoV-2, combined those data with the previously known protein-protein interaction data (expected to be involved in virus replication) and generated the RNA-protein-protein interaction (RPPI) network. Analysis of the RPPI network revealed the enrichment of factors involved in translation initiation and RNA metabolism, which are important for virus replication. Analysis of one of the interaction partners of the 5’-UTR (Lamp2a) demonstrated its antiviral role in SARS-CoV-2 infected cells. Collectively, our study provides a resource of SARS-CoV-2 UTR-binding proteins and identifies an antiviral role of host Lamp2a protein.

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Section: Discussionsupporting

confidence: 84%

RNA-protein interaction analysis of SARS-CoV-2 5’- and 3’-untranslated regions identifies an antiviral role of lysosome-associated membrane protein-2

Verma

Saha

Kumar

et al. 2021

Preprint

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“…This redirected the Rab7-containing vesicles to the plus-end-directed kinesin motor for anterograde movement towards the plasma membrane to promote virion secretion 66 . HCV has been shown to exploit autophagy and enhance virus production; it was also shown that redirecting lysosomes towards the host cell periphery inhibited the overall autophagic flux in HCV-infected cells 69 . Therefore, HCV and S. Typhimurium appeared to recruit the kinesin motors to their compartments to facilitate their anterograde trafficking towards the plasma membrane and promote cell-to-cell spread.…”

Section: Discussionmentioning

confidence: 99%

Lysosome repositioning as an autophagy escape mechanism by Mycobacterium tuberculosis Beijing strain

Laopanupong

Prombutara

Kanjanasirirat

et al. 2021

Sci Rep

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Induction of host cell autophagy by starvation was shown to enhance lysosomal delivery to mycobacterial phagosomes, resulting in the restriction of Mycobacterium tuberculosis reference strain H37Rv. Our previous study showed that strains belonging to M. tuberculosis Beijing genotype resisted starvation-induced autophagic elimination but the factors involved remained unclear. Here, we conducted RNA-Seq of macrophages infected with the autophagy-resistant Beijing strain (BJN) compared to macrophages infected with H37Rv upon autophagy induction by starvation. Results identified several genes uniquely upregulated in BJN-infected macrophages but not in H37Rv-infected cells, including those encoding Kxd1 and Plekhm2, which function in lysosome positioning towards the cell periphery. Unlike H37Rv, BJN suppressed enhanced lysosome positioning towards the perinuclear region and lysosomal delivery to its phagosome upon autophagy induction by starvation, while depletion of Kxd1 and Plekhm2 reverted such effects, resulting in restriction of BJN intracellular survival upon autophagy induction by starvation. Taken together, these data indicated that Kxd1 and Plekhm2 are important for the BJN strain to suppress lysosome positioning towards the perinuclear region and lysosomal delivery into its phagosome during autophagy induction by starvation to evade starvation-induced autophagic restriction.

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“…Multiple studies have indicated that the fusion of autophagosomes with lysosomes is delayed in HCV-infected cells, resulting in the accumulation of autophagosomes in the early stage of HCV infection [ 20 , 35 , 38 , 47 , 48 ]. This delayed maturation of autophagosomes in HCV-infected cells was found to be due to the differential induction of Rubicon and UVRAG proteins by HCV [ 38 , 48 ].…”

Section: Biogenesis Of Autophagosomes Induced By Hcvmentioning

confidence: 99%

“…However, in the late stage of infection, UVRAG was also upregulated to overcome the inhibitory effect of Rubicon, resulting in the maturation of autophagosomes and the completion of the autophagic flux [ 38 ]. Jones-Jamtgaard et al also reported that Arl8b, an Arf-like GTPase that localizes to lysosomes and regulates the autophagic flux, was redistributed by HCV to peripheral locations to suppress the autophagosome–lysosome fusion [ 47 ]. These studies indicated that HCV could use different mechanisms to delay the maturation of autophagosomes and suppress the autophagic flux.…”

Section: Biogenesis Of Autophagosomes Induced By Hcvmentioning

confidence: 99%

Autophagy in HCV Replication and Protein Trafficking

Chu

2021

IJMS

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Autophagy is a catabolic process that is important for maintaining cellular homeostasis. It is also known to possess other functions including protein trafficking and anti-microbial activities. Hepatitis C virus (HCV) is known to co-opt cellular autophagy pathway to promote its own replication. HCV regulates autophagy through multiple mechanisms to control intracellular protein and membrane trafficking to enhance its replication and suppress host innate immune response. In this review, we discuss the current knowledge on the interplay between HCV and autophagy and the crosstalk between HCV-induced autophagy and host innate immune responses.

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Hepatitis C virus infection increases autophagosome stability by suppressing lysosomal fusion through an Arl8b-dependent mechanism

Cited by 19 publications

References 43 publications

RNA-protein interaction analysis of SARS-CoV-2 5’- and 3’-untranslated regions identifies an antiviral role of lysosome-associated membrane protein-2

RNA-protein interaction analysis of SARS-CoV-2 5’- and 3’-untranslated regions identifies an antiviral role of lysosome-associated membrane protein-2

Lysosome repositioning as an autophagy escape mechanism by Mycobacterium tuberculosis Beijing strain

Autophagy in HCV Replication and Protein Trafficking

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