How Viruses Use the VCP/p97 ATPase Molecular Machine

Das, Poulami; Dudley, Jaquelin P.

doi:10.3390/v13091881

“…We found CB-5083 to inhibit RSV replication in both A549 and Hela-H1 cells ( Figures 2B,D ), as well as to block the replication of VSV ( Figure 2E ). These results further support VCP/p97 as a general target for antiviral therapy against different viruses ( Das and Dudley, 2021 ). To gain insights into the step of the replication cycle where VCP/p97 acts, we examined the effect of adding CB-5083 before or after viral entry.…”

Section: Discussionsupporting

confidence: 70%

Identification of Cytoplasmic Chaperone Networks Relevant for Respiratory Syncytial Virus Replication

Latorre

¹

,

Geller

²

2022

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RNA viruses have limited coding capacity and must therefore successfully subvert cellular processes to facilitate their replication. A fundamental challenge faced by both viruses and their hosts is the ability to achieve the correct folding and assembly of their proteome while avoiding misfolding and aggregation. In cells, this process is facilitated by numerous chaperone systems together with a large number of co-chaperones. In this work, we set out to define the chaperones and co-chaperones involved in the replication of respiratory syncytial virus (RSV). Using an RNAi screen, we identify multiple members of cellular protein folding networks whose knockdown alters RSV replication. The reduced number of chaperones and co-chaperones identified in this work can facilitate the unmasking of specific chaperone subnetworks required for distinct steps of the RSV life cycle and identifies new potential targets for antiviral therapy. Indeed, we show that the pharmacological inhibition of one of the genes identified in the RNAi screen, valosin-containing protein (VCP/p97), can impede the replication of RSV by interfering with the infection cycle at multiple steps.

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“…2E). These results further support VCP/p97 as a general target for antiviral therapy against different viruses (Das and Dudley, 2021). To gain insights into the step of the replication cycle where VCP/p97 acts, we examined the effect of adding CB-5083 before or after viral entry.…”

Section: Discussionsupporting

confidence: 70%

Identification of cytoplasmic chaperone networks relevant for respiratory syncytial virus replication

Latorre

¹

,

Geller

²

2022

Preprint

0

View full text Add to dashboard Cite

RNA viruses have limited coding capacity and must therefore successfully subvert cellular processes to facilitate their replication. A fundamental challenge faced by both viruses and their hosts is the ability to achieve the correct folding and assembly of their proteome while avoiding misfolding and aggregation. In cells, this process is facilitated by numerous chaperone systems together with a large number of co-chaperones. In this work, we set out to define the chaperones and co-chaperones involved in the replication of respiratory syncytial virus (RSV). Using an RNAi screen, we identify multiple members of cellular protein folding networks whose knockdown alters RSV replication. The reduced number of chaperones and co-chaperones identified in this work can facilitate the unmasking of specific chaperone subnetworks required for distinct steps of the RSV life cycle and identifies new potential targets for antiviral therapy. Indeed, we show that the pharmacological inhibition of one of the genes identified in the RNAi screen, valosin-containing protein (VCP/p97), can impede the replication of RSV by interfering with the infection cycle at multiple steps.

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“…Consistently, mammalian Pelo has also been shown to be important for DENV and BVDV viral replication ( Asad et al, 2018 ). VCP, another key component of the RQC pathway, has also been implicated in various steps in the viral life cycle, from entry and uncoating to viral egress ( Das and Dudley, 2021 ). However, whether these factors act through canonical RQC activity to modulate viral function remains to be established.…”

Section: Translational Regulation and Ribosome-associated Quality Con...mentioning

confidence: 99%

Translational regulation by ribosome-associated quality control in neurodegenerative disease, cancer, and viral infection

Lu

¹

2022

Front. Cell Dev. Biol.

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Translational control at the initiation, elongation, and termination steps exerts immediate effects on the rate as well as the spatiotemporal dynamics of new protein synthesis, shaping the composition of the proteome. Translational control is particularly important for cells under stress as during viral infection or in disease conditions such as cancer and neurodegenerative diseases. Much has been learned about the control mechanisms acting at the translational initiation step under normal or pathological conditions. However, problems during the elongation or termination steps of translation can lead to ribosome stalling and ribosome collision, which will trigger ribosome-associated quality control (RQC) mechanism. Inadequate RQC may lead to the accumulation of faulty translation products that perturb protein homeostasis (proteostasis). Proteostasis signifies a cellular state in which the synthesis, folding, and degradation of proteins are maintained at a homeostatic state such that an intact proteome is preserved. Cellular capacity to preserve proteostasis declines with age, which is thought to contribute to age-related diseases. Proteostasis failure manifested as formation of aberrant protein aggregates, epitomized by the amyloid plaques in Alzheimer’s disease (AD), is a defining feature of neurodegenerative diseases. The root cause of the proteostasis failure and protein aggregation is still enigmatic. Here I will review recent studies supporting that faulty translation products resulting from inadequate RQC of translational stalling and ribosome collision during the translation of problematic mRNAs can be the root cause of proteostasis failure and may represent novel therapeutic targets for neurodegenerative diseases. I will also review evidence that translation regulation by RQC is operative in cancer cells and during viral infection. Better understanding of RQC mechanism may lead to novel therapeutic strategies against neurodegenerative diseases, cancer, and viral infections, including the ongoing COVID-19 pandemic.

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How Viruses Use the VCP/p97 ATPase Molecular Machine

Cited by 15 publications

References 175 publications

Identification of Cytoplasmic Chaperone Networks Relevant for Respiratory Syncytial Virus Replication

Identification of Cytoplasmic Chaperone Networks Relevant for Respiratory Syncytial Virus Replication

Identification of cytoplasmic chaperone networks relevant for respiratory syncytial virus replication

Translational regulation by ribosome-associated quality control in neurodegenerative disease, cancer, and viral infection

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