Characterization of the Second Apoptosis Inhibitor Encoded by Guinea Pig Cytomegalovirus

Satoh, Katsuya; Takahashi, Keita; Noguchi, Kazuma; Kobayashi, Yuhki; Majima, Ryuichi; Iwase, Yoshihiko; Yamaguchi, Kazuya; Masuda, Yukina; Koshizuka, Tetsuo; Inoue, Naoki

doi:10.1128/jvi.01622-22

J Virol

2022

DOI: 10.1128/jvi.01622-22

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Characterization of the Second Apoptosis Inhibitor Encoded by Guinea Pig Cytomegalovirus

Katsuya Satoh

Keita Takahashi

Kazuma Noguchi

et al.

Abstract: Although GPCMV provides a useful animal model for studies on the pathogenesis of congenital CMV infection and the development of CMV vaccine strategies, our understanding of the viral mechanisms by which it evades apoptosis of infected cells has been limited in comparison with those of murine and human CMVs. Here, we report a second GPCMV apoptosis inhibitor (42 amino acids in length) that interacts with BAK, a Bcl-2 family proapoptotic protein.

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2024

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Cited by 3 publications

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Downregulation of CD86 in HCMV‐infected THP‐1 cells

Koshizuka,

Sasaki,

Kondo

et al. 2024

Microbiology and Immunology

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Monocytes and macrophages are at the frontline of defense against pathogens. Human cytomegalovirus (HCMV) uses myeloid cells as vehicles to facilitate viral dissemination. HCMV infection in monocytes and macrophages leads to the downregulation of several cell surface markers via an undefined mechanism. Previously, we showed that HCMV pUL42 associates with the Nedd4 family ubiquitin E3 ligases through the PPXY motif on pUL42 and downregulates Nedd4 and Itch proteins in HCMV‐infected fibroblasts. Homologous proteins of HCMV pUL42, such as HHV‐6 U24, downregulate cell surface markers. To reveal the downregulation property of pUL42, we focused on CD86, the key costimulatory factor for acquired immunity. Here, we constructed CD86‐expressing THP‐1 cells using a retroviral vector and analyzed the effects of HCMV infection and pUL42 on CD86 downregulation. Disruption of the PPXY motifs of pUL42 (UL42PA) decelerated the degradation of CD86 in recombinant virus‐infected cells, indicating the involvement of Nedd4 family functions. However, no direct interactions were observed between CD86 and Itch. Interestingly, unlike fibroblast infection, the expression of Nedd4 and Itch proteins increased in HCMV‐infected THP‐1 cells, accompanied by an increase in their transcript levels. Although the function of pUL42 did not relate to the increase of Nedd4 and Itch proteins, pUL42 should affect these Nedd4 proteins to downregulate CD86.

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Downregulation of CD86 in HCMV‐infected THP‐1 cells

Koshizuka,

Sasaki,

Kondo

et al. 2024

Microbiology and Immunology

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No Time to Die: How Cytomegaloviruses Suppress Apoptosis, Necroptosis, and Pyroptosis

Deng,

Águeda-Pinto,

Brune

2024

Viruses

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Viruses are obligate intracellular pathogens as their replication depends on the metabolism of the host cell. The induction of cellular suicide, known as programmed cell death (PCD), has the potential to hinder viral replication and act as a first line of defense against viral pathogens. Apoptosis, necroptosis, and pyroptosis are three important PCD modalities. Different signaling pathways are involved in their execution, and they also differ in their ability to cause inflammation. Cytomegaloviruses (CMV), beta-herpesviruses with large double-stranded DNA genomes, encode a great variety of immune evasion genes, including several cell death suppressors. While CMV inhibitors of apoptosis and necroptosis have been known and studied for years, the first pyroptosis inhibitor has been identified and characterized only recently. Here, we describe how human and murine CMV interfere with apoptosis, necroptosis, and pyroptosis signaling pathways. We also discuss the importance of the different PCD forms and their viral inhibitors for the containment of viral replication and spread in vivo.

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Cytomegalovirus Biology Viewed Through a Cell Death Suppression Lens

Mocarski

2024

Viruses

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Cytomegaloviruses, species-specific members of the betaherpesviruses, encode an impressive array of immune evasion strategies committed to the manipulation of the host immune system enabling these viruses to remain for life in a stand-off with host innate and adaptive immune mechanisms. Even though they are species-restricted, cytomegaloviruses are distributed across a wide range of different mammalian species in which they cause systemic infection involving many different cell types. Regulated, or programmed cell death has a recognized potential to eliminate infected cells prior to completion of viral replication and release of progeny. Cell death also naturally terminates replication during the final stages of replication. Over the past two decades, the host defense potential of known programmed cell death pathways (apoptosis, necroptosis, and pyroptosis), as well as a novel mitochondrial serine protease pathway have been defined through studies of cytomegalovirus-encoded cell death suppressors. Such virus-encoded inhibitors prevent virus-induced, cytokine-induced, and stress-induced death of infected cells while also moderating inflammation. By evading cell death and consequent inflammation as well as innate and adaptive immune clearance, cytomegaloviruses represent successful pathogens that become a critical disease threat when the host immune system is compromised. This review will discuss cell death programs acquired for mammalian host defense against cytomegaloviruses and enumerate the range of modulatory strategies this type of virus employs to balance host defense in favor of lifelong persistence.

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Characterization of the Second Apoptosis Inhibitor Encoded by Guinea Pig Cytomegalovirus

Cited by 3 publications

References 45 publications

Downregulation of CD86 in HCMV‐infected THP‐1 cells

Downregulation of CD86 in HCMV‐infected THP‐1 cells

No Time to Die: How Cytomegaloviruses Suppress Apoptosis, Necroptosis, and Pyroptosis

Cytomegalovirus Biology Viewed Through a Cell Death Suppression Lens

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