Inhibition of ULK1 and Beclin1 by an α-herpesvirus Akt-like Ser/Thr kinase limits autophagy to stimulate virus replication

Rubio, Rosa M.; Mohr, Ian

doi:10.1073/pnas.1915139116

Cited by 33 publications

(35 citation statements)

References 66 publications

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“…Interestingly, in the non-neuronal cells, inhibition of autophagy was achieved by the phosphorylation of two autophagy regulators: ULK1 and Beclin1, which are dependent on the HSV-1 protein Us3 ser/thr kinase. The authors also showed that depleting both ULK1 and Beclin1 rescued the replication of the Us3-deficient virus strain [ 49 ]. This is significant, as Us3 also plays a role in viral manipulation of cellular apoptosis [ 50 ].…”

Section: Hsv Immune Evasion Mechanismsmentioning

confidence: 99%

Immune Response to Herpes Simplex Virus Infection and Vaccine Development

et al. 2020

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Herpes simplex virus (HSV) infections are among the most common viral infections and usually last for a lifetime. The virus can potentially be controlled with vaccines since humans are the only known host. However, despite the development and trial of many vaccines, this has not yet been possible. This is normally attributed to the high latency potential of the virus. Numerous immune cells, particularly the natural killer cells and interferon gamma and pathways that are used by the body to fight HSV infections have been identified. On the other hand, the virus has developed different mechanisms, including using different microRNAs to inhibit apoptosis and autophagy to avoid clearance and aid latency induction. Both traditional and new methods of vaccine development, including the use of live attenuated vaccines, replication incompetent vaccines, subunit vaccines and recombinant DNA vaccines are now being employed to develop an effective vaccine against the virus. We conclude that this review has contributed to a better understanding of the interplay between the immune system and the virus, which is necessary for the development of an effective vaccine against HSV.

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Section: Hsv Immune Evasion Mechanismsmentioning

confidence: 99%

Immune Response to Herpes Simplex Virus Infection and Vaccine Development

et al. 2020

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“…It would be worth testing the hypothesis that this feedback is mitigated in severe COVID-19 by modulation of autophagy ( 81 ), and inhibition of molecules like ULK1 by SARS-CoVs ( Table 2 ), in as much they can infect activated/memory T cells expressing CD147. Indeed, HSV-1 can inhibit ULK1 to escape the autophagy process ( 82 ), and previous studies on other betacoronaviruses showed that, upon cell infection, these viruses inhibit macro-autophagy ( 83 ). For instance, the porcine hemagglutinating encephalomyelitis (PHEV) betacoronavirus inhibits the expression of the ULK1 protein ( 84 ).…”

Section: Introductionmentioning

confidence: 99%

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

et al. 2020

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Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.

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“…Additionally, BECN1 promotes fusion of the autophagosome with the lysosome for content degradation [85]. Proteins of negative-sense RNA viruses and DNA viruses, including Influenza A M2, HIV nef, and HSV-1 ICP34.5, target BECN1 to inhibit either nucleation of the autophagosome or fusion of the autophagosome with the lysosome to increase viral replication [86][87][88][89]. BECN1 negatively regulates the innate immune response with CGAS by preventing excessive IFN (interferon) production while promoting autophagic degradation of intracellular pathogens such as HSV-1 (Figure 1) [90].…”

Section: Coronaviruses and Becn1mentioning

confidence: 99%

Coronavirus interactions with the cellular autophagy machinery

et al. 2020

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The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is the most recent example of an emergent coronavirus that poses a significant threat to human health. Virus-host interactions play a major role in the viral life cycle and disease pathogenesis, and cellular pathways such as macroautophagy/autophagy prove to be either detrimental or beneficial to viral replication and maturation. Here, we describe the literature over the past twenty years describing autophagy-coronavirus interactions. There is evidence that many coronaviruses induce autophagy, although some of these viruses halt the progression of the pathway prior to autophagic degradation. In contrast, other coronaviruses usurp components of the autophagy pathway in a non-canonical fashion. Cataloging these virus-host interactions is crucial for understanding disease pathogenesis, especially with the global challenge of SARS-CoV-2 and COVID-19. With the recognition of autophagy inhibitors, including the controversial drug chloroquine, as possible treatments for COVID-19, understanding how autophagy affects the virus will be critical going forward.

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Inhibition of ULK1 and Beclin1 by an α-herpesvirus Akt-like Ser/Thr kinase limits autophagy to stimulate virus replication

Cited by 33 publications

References 66 publications

Immune Response to Herpes Simplex Virus Infection and Vaccine Development

Immune Response to Herpes Simplex Virus Infection and Vaccine Development

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

Coronavirus interactions with the cellular autophagy machinery

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