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      BK Polyomavirus Evades Innate Immune Sensing by Disrupting the Mitochondrial Network and Promotes Mitophagy

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          Summary

          Immune escape contributes to viral persistence, yet little is known about human polyomaviruses. BK-polyomavirus (BKPyV) asymptomatically infects 90% of humans but causes premature allograft failure in kidney transplant patients. Despite virus-specific T cells and neutralizing antibodies, BKPyV persists in kidneys and evades immune control as evidenced by urinary shedding in immunocompetent individuals. Here, we report that BKPyV disrupts the mitochondrial network and membrane potential when expressing the 66aa-long agnoprotein during late replication. Agnoprotein is necessary and sufficient, using its amino-terminal and central domain for mitochondrial targeting and network disruption, respectively. Agnoprotein impairs nuclear IRF3-translocation, interferon-beta expression, and promotes p62/SQSTM1-mitophagy. Agnoprotein-mutant viruses unable to disrupt mitochondria show reduced replication and increased interferon-beta expression but can be rescued by type-I interferon blockade, TBK1-inhibition, or CoCl 2-treatment. Mitochondrial fragmentation and p62/SQSTM1-autophagy occur in allograft biopsies of kidney transplant patients with BKPyV nephropathy. JCPyV and SV40 infection similarly disrupt mitochondrial networks, indicating a conserved mechanism facilitating polyomavirus persistence and post-transplant disease.

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          Highlights

          • •

            BK polyomavirus agnoprotein disrupts mitochondrial membrane potential and network

          • •

            Agnoprotein impairs nucleus IRF3 translocation and interferon-β expression

          • •

            Agnoprotein facilitates innate immune evasion during the late viral replication phase

          • •

            Damaged mitochondria are targeted for p62/SQSTM1 autophagy

          Abstract

          Biological Sciences; Immunology; Virology; Cell Biology

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          Most cited references63

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          DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity.

          Anetta Härtlová, Saskia Erttmann, Faizal Raffi … (2015)
          Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.
          Article 0 comments Cited 329 times – based on 0 reviews     Review now
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            Selective autophagy mediated by autophagic adapter proteins.

            Terje Johansen, Trond Lamark (2011)
            Mounting evidence suggests that autophagy is a more selective process than originally anticipated. The discovery and characterization of autophagic adapters, like p62 and NBR1, has provided mechanistic insight into this process. p62 and NBR1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. A direct interaction between these autophagic adapters and the autophagosomal marker protein LC3, mediated by a so-called LIR (LC3-interacting region) motif, their inherent ability to polymerize or aggregate as well as their ability to specifically recognize substrates are required for efficient selective autophagy. These three required features of autophagic cargo receptors are evolutionarily conserved and also employed in the yeast cytoplasm-to-vacuole targeting (Cvt) pathway and in the degradation of P granules in C. elegans. Here, we review the mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria. The emerging picture of selective autophagy affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is also addressed.
            Article 0 comments Cited 306 times – based on 0 reviews     Review now
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              The virome in mammalian physiology and disease.

              Herbert Virgin (2014)
              The virome contains the most abundant and fastest mutating genetic elements on Earth. The mammalian virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. Virome interactions with the host cannot be encompassed by a monotheistic view of viruses as pathogens. Instead, the genetic and transcriptional identity of mammals is defined in part by our coevolved virome, a concept with profound implications for understanding health and disease. Copyright © 2014 Elsevier Inc. All rights reserved.
              Article 0 comments Cited 256 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Hans H. Hirsch
                Journal
                Journal ID (nlm-ta): iScience
                Journal ID (iso-abbrev): iScience
                Title: iScience
                Publisher: Elsevier
                ISSN (Electronic): 2589-0042
                Publication date PMC-release: 10 June 2020
                Publication date Collection: 24 July 2020
                Publication date (Electronic): 10 June 2020
                Volume: 23
                Issue: 7
                Electronic Location Identifier: 101257
                Affiliations
                [1 ]Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10, CH-4009 Basel, Switzerland
                [2 ]Institute for Pathology, University Hospital Basel, Basel, Switzerland
                [3 ]Departments of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
                [4 ]Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway
                [5 ]Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
                [6 ]Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
                [7 ]Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
                Author notes
                [∗ ]Corresponding author hans.hirsch@ 123456unibas.ch
                [8]

                Present address: Cancer Immunotherapy, Department Biomedicine, University of Basel, Basel, Switzerland

                [9]

                Present address: Immunobiology, Department Biomedicine, University of Basel, Basel, Switzerland

                [10]

                Lead contact

                Article
                Publisher ID: S2589-0042(20)30443-0 Publisher ID: 101257
                DOI: 10.1016/j.isci.2020.101257
                PMC ID: 7326741
                PubMed ID: 32599557
                SO-VID: 7b0b8dc5-469d-46a6-89d0-5ee30fcd6938
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 10 September 2019
                Date revision received : 16 March 2020
                Date accepted : 5 June 2020
                Categories
                Subject: Article

                Keywords: biological sciences,immunology,virology,cell biology
                Data availability:
                Keywords: biological sciences, immunology, virology, cell biology

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