HHV-7 U21 exploits Golgi quality control carriers to reroute class I MHC molecules to lysosomes

Dirck, Aaron T.; Whyte, Melissa L.; Hudson, Amy W.

doi:10.1091/mbc.e19-07-0363

Cited by 7 publications

(4 citation statements)

References 57 publications

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“…While HLA-A2 complexes tagged with RUSH typically localize to the cell membrane after leaving the Golgi in tubules, RUSH-tagged HLA-A2 complexes were absent from tubules when co-expressed with RUSH-tagged U21. However, HLA-A2 was present in all vesicles containing RUSH-tagged U21 [ 133 ].…”

Section: Immune Cell Responsesmentioning

confidence: 99%

“…It had previously been established that U21 oligomerizes with MHC class I complexes [ 134 ] and that oligomerized Golgi proteins are targeted to lysosomes for degradation [ 135 ]. This led to the hypothesis that the U21/MHC class I oligomers exit the Golgi apparatus in lysosome-bound vesicles [ 133 ]. Specifically, the authors postulated that the U21/MHC class I oligomers exited the Golgi apparatus in quality control carriers.…”

Section: Immune Cell Responsesmentioning

confidence: 99%

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Evasion of the Host Immune Response by Betaherpesviruses

Sausen

Reed

Bhutta

et al. 2021

IJMS

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The human immune system boasts a diverse array of strategies for recognizing and eradicating invading pathogens. Human betaherpesviruses, a highly prevalent subfamily of viruses, include human cytomegalovirus (HCMV), human herpesvirus (HHV) 6A, HHV-6B, and HHV-7. These viruses have evolved numerous mechanisms for evading the host response. In this review, we will highlight the complex interplay between betaherpesviruses and the human immune response, focusing on protein function. We will explore methods by which the immune system first responds to betaherpesvirus infection as well as mechanisms by which viruses subvert normal cellular functions to evade the immune system and facilitate viral latency, persistence, and reactivation. Lastly, we will briefly discuss recent advances in vaccine technology targeting betaherpesviruses. This review aims to further elucidate the dynamic interactions between betaherpesviruses and the human immune system.

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Section: Immune Cell Responsesmentioning

confidence: 99%

Section: Immune Cell Responsesmentioning

confidence: 99%

Evasion of the Host Immune Response by Betaherpesviruses

Sausen

Reed

Bhutta

et al. 2021

IJMS

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“…Cells were plated as previously described [19]. Five hours post-transfection, live cells were imaged on a Nikon Eclipse Ti2 microscope equipped with a W1 Spinning Disc, Orca Flash CMOS camera, and 60× oil-immersion objective (CFI Plan Apo λ, 1.4 NA objective) confocal microscope, as previously described [41]. Live-cell images were obtained every 10 seconds.…”

Section: Live-cell Imagingmentioning

confidence: 99%

Resolution of Two Steps in Botulinum Neurotoxin Serotype A1 Light Chain Localization to the Intracellular Plasma Membrane

Gardner

Tepp

Bradshaw

et al. 2021

IJMS

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Botulinum neurotoxin serotype A (BoNT/A) is the most potent protein toxin to humans. BoNT/A light chain (LC/A) cleavage of the membrane-bound SNAP-25 has been well-characterized, but how LC/A traffics to the plasma membrane to target SNAP-25 is unknown. Of the eight BoNT/A subtypes (A1–A8), LC/A3 has a unique short duration of action and low potency that correlate to the intracellular steady state of LC/A, where LC/A1 is associated with the plasma membrane and LC/A3 is present in the cytosol. Steady-state and live imaging of LC/A3-A1 chimeras identified a two-step process where the LC/A N terminus bound intracellular vesicles, which facilitated an internal α-helical-rich domain to mediate LC/A plasma membrane association. The propensity of LC/A variants for membrane association correlated with enhanced BoNT/A potency. Understanding the basis for light chain intracellular localization provides insight to mechanisms underlying BoNT/A potency, which can be extended to applications as a human therapy.

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“…HHV-6 and 7 lack positional homologs of HCMV host evasion proteins, and instead contain several blocks of genes unique to the roseoloviruses, some of which have been shown to encode proteins involved in evasion of host defenses (15)(16)(17)(18)(19)(20). For example, the U21 open reading frame from HHV-6A, 6B and 7 is a type I integral membrane protein that reroutes class I MHC to lysosomes or degradation (15,18,21). The same U21 protein has been shown to downregulate NK activating ligands and Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the HHV-6 U20 immunoevasin

Schneider

Whyte

Konrad

et al. 2022

Preprint

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Roseoloviruses (HHV-6A, -6B, and -7) infect >90% of the human population during early childhood, and are thought to remain latent or persistent throughout the life of the host. As such, these viruses are among the most pervasive and stealthy of all viruses; they must necessarily excel at escaping immune detection throughout the life of the host, and yet very little is known about how these viruses so successfully escape host defenses. Herein, we characterize the HHV6A and HHV6B U20 gene products, which are encoded within a block of genes unique to the roseoloviruses, and therefore of particular interest. Despite 92% amino acid identity, U20 proteins from HHV6A and 6B have been shown to possess different host evasion functions. Here we characterize expression, trafficking, and post-translational modifications of U20 during HHV6A infection. While U20 localized to lysosomes in HHV-6A-infected cells, HHV-6B U20 trafficked to the cell surface and was rapidly internalized. HHV-6B U20 trafficked slowly through the secretory system, receiving several post translational modifications to its N-linked glycans indicative of surface expressed glycoproteins. Interestingly, U20 is also phosphorylated on at least one Ser, Thr, or Tyr residue. These results provide a framework to understand the role(s) of U20 in evading host defenses.

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HHV-7 U21 exploits Golgi quality control carriers to reroute class I MHC molecules to lysosomes

Abstract: U21 is a viral protein that forms hetero-oligomers with class I major histocompatibility complex molecules and reroutes them to lysosomes. It is shown that U21 exits from the Golgi in a distinct clathrin-independent carrier that also carries unfolded and aggregated proteins to lysosomes.

Cited by 7 publications

References 57 publications

Evasion of the Host Immune Response by Betaherpesviruses

Evasion of the Host Immune Response by Betaherpesviruses

Resolution of Two Steps in Botulinum Neurotoxin Serotype A1 Light Chain Localization to the Intracellular Plasma Membrane

Characterization of the HHV-6 U20 immunoevasin

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