The transporter associated with antigen processing: a key player in adaptive immunity

Eggensperger, Sabine; Tampé, Robert

doi:10.1515/hsz-2014-0320

Cited by 64 publications

(55 citation statements)

References 121 publications

(158 reference statements)

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“…ICP0 induces degradation of CD83, a marker of DC maturation, resulting in reduced T-cell stimulation [71]. ICP47 down-regulates MHC I-peptide presentation by blocking transporter associated with antigen presentation (TAP) in infected human cells, including cancer cells [7]. This results in no MHC I-mediated antigen presentation to CD8 + T-cells and escape from immune surveillance [7].…”

Section: Hsv Evasion Of Host Antiviral Responsesmentioning

confidence: 99%

“…ICP47 down-regulates MHC I-peptide presentation by blocking transporter associated with antigen presentation (TAP) in infected human cells, including cancer cells [7]. This results in no MHC I-mediated antigen presentation to CD8 + T-cells and escape from immune surveillance [7]. Inhibition of mouse TAP with oHSV expressing bovine herpes virus UL49.5 improved anti-tumor efficacy in syngeneic tumor models, dependent on CD8+ T-cells, and with increased virus [72*].…”

Section: Hsv Evasion Of Host Antiviral Responsesmentioning

confidence: 99%

“…The cascade of host responses against HSV infection, which applies to oHSV, includes: serum factors (complement proteins and innate immunoglobulins); innate cytokine/chemokine cascades; recruitment and activation of innate immune cells; and induction of adaptive immune responses [5,6] (Figure 1). As a successful pathogen, HSV has multiple mechanisms to evade such host responses: inactivation of complement and immunoglobulins by viral glycoproteins; inhibition of interferon (IFN) responses and cytokine/chemokine production from infected cells [5]; blocking maturation of antigen presenting cells (APCs) [6]; escape from host immune surveillance through down-regulation of MHC class I expression [7]; and inhibition of apoptosis and cytotoxic T lymphocyte (CTL)-induced cell death [8]. A better understanding of the complex landscape of virus-host interaction is thus essential to refine oHSV strategies to improve therapeutic outcomes and understand oHSV immune vulnerabilities.…”

Section: Introductionmentioning

confidence: 99%

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Oncolytic herpes simplex virus interactions with the host immune system

Saha

Wakimoto

Rabkin

2016

Current Opinion in Virology

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Oncolytic viruses (OVs), like oncolytic herpes simplex virus (oHSV), are genetically engineered to selectively replicate in and kill cancer cells, while sparing normal cells. Initial OV infection, cell death, and subsequent OV propagation within the tumor microenvironment leads to a cascade of host responses (innate and adaptive), reflective of natural anti-viral immune responses. These host-virus interactions are critical to the balance between OV activities, anti-viral immune responses limiting OV, and induction of anti-tumor immunity. The host response against oHSV is complex, multifaceted, and modulated by the tumor microenvironment and immunosuppression. As a successful pathogen, HSV has multiple mechanisms to evade such host responses. In this review, we will discuss these mechanisms and HSV evasion, and how they impact oHSV therapy.

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Section: Hsv Evasion Of Host Antiviral Responsesmentioning

confidence: 99%

Section: Hsv Evasion Of Host Antiviral Responsesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oncolytic herpes simplex virus interactions with the host immune system

Saha

Wakimoto

Rabkin

2016

Current Opinion in Virology

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“…For both DRiPs and retirees, proteasome degradation plays an important role in generating cytosolic peptides of between 8 and ~ 17 residues that can be transported into the ER by TAP (6). Classically, proteins are targeted for proteasome degradation by covalent addition of ubiquitin (Ub).…”

Section: Introductionmentioning

confidence: 99%

Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands

Wei

Zanker

Carluccio

et al. 2017

The Journal of Immunology

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CD8+ T cell immunosurveillance is based on recognizing oligopeptides presented by MHC class I molecules. Despite decades of study, the importance of protein ubiquitylation to peptide generation remains uncertain. Here, we examine the ability of MLN7243, a recently described ubiquitin activating enzyme E1-inhibitor, to block overall cytosolic peptide generation and generation of specific peptides from vaccinia- and influenza A virus-encoded proteins. We show that MLN7243 rapidly inhibits ubiquitylation in a variety of cell lines, and can profoundly reduce generation of cytosolic peptides. Kinetic analysis of specific peptide generation reveals that ubiquitylation of defective ribosomal products (DRiPs) is rate limiting in generating class I peptide complexes. More generally, our findings demonstrate that the requirement for ubiquitylation in MHC class I restricted antigen processing varies with class I allomorph, cell type, source protein, and peptide context. Thus, both ubiquitin-dependent and independent pathways robustly contribute to MHC class I based immunosurveillance.

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“…The large size of T1SS substrates suggest that the transporter operates in a distinct mechanism from peptide ABC transporters such as microcin exporters and the human antigen transporters, TAP1/2 (Choudhury et al, 2014;Grossmann et al, 2014;Eggensperger and Tampe, 2015;Lin et al, 2015). These transporters appear to operate by the 'alternating access' mechanism whereby the peptide binds from the cytoplasmic side (Rees et al, 2009;Beek et al, 2014;Locher, 2016).…”

Section: Octyl Udp-6-thio-α-d-galactopyranose Disulfide (7)mentioning

confidence: 99%

Structural Studies of Biopolymer Membrane Transport

Morgan¹

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The selective transport of specific substrates across the membrane is an essential part of biology.Organisms have evolved a basic mechanism for the transport of ions and small molecule such as sugars across the membrane. This mechanism is termed 'alternating access' and involves the alternating exposure of a substrate-binding site to either side of the membrane. While the molecular details of 'alternating access' have been revealed for a number of different transporters, this scheme seems infeasible for the transport of long biopolymers such as nucleic acids, proteins, and polysaccharides because 'alternating access' requires that the transporter forms a binding site that is large enough to bind the entire substrate. Here, I present novel data addressing the transport mechanism for two bacterial biopolymer transporter proteins: Bacterial Cellulose Synthase which synthesizes and secretes the polysaccharide, cellulose; and PrtD, an ABC transporter which is involved in the secretion of an extracellular protease.Cellulose is a linear polymer of glucose units that forms a major component of plant cell walls as well as many bacterial biofilms. In bacteria, the components required for cellulose biosynthesis are encoded in a single operon minimally made up of the genes bcsA, bcsB, bcsC, and bcsZ. BcsA is an integral inner-membrane (IM) glycosyltransferase enzyme that is responsible for coupling the synthesis of cellulose with its transport across the IM. BcsB is a periplasmic protein with Cterminal IM anchor, and BcsB forms a complex with BcsA (BcsA-B) that is sufficient for in vitro cellulose synthesis. BcsZ is a periplasmic cellulase enzyme, and BcsC is an outer-membrane β-barrel that presumably forms a pore for the cellulose polymer to cross the outer membrane.iii BcsA-B activity is stimulated by the bacterial signaling molecule, cyclic-di-GMP (c-di-GMP), which is a key regulator of biofilm formation. I present crystal structures of the c-di-GMP-bound BcsA-B complex in the presence and absence of UDP, a competitive inhibitor and substrate mimic. The structures reveal that c-di-GMP releases an auto-inhibited state of the enzyme. A salt bridge stabilizes one of the signature c-di-GMP-binding Arg residues in a position to tether a conserved 'gating loop' in front of the active site. The binding of c-di-GMP releases the tether and allows substrate to access the active site. Additionally, the UDP-bound structure reveals an additional role for the 'gating loop' in coordinating substrate at the active site. Functional experiments confirm the structural interpretation by revealing that disruption of the auto-inhibitory salt bridge by mutagenesis generates a constitutively-active cellulose synthase. The mechanistic insights presented here represent the first examples of how c-di-GMP allosterically modulates enzymatic functions.To address the mechanism by which BcsA-B transports cellulose across the IM, I use in crystallo enzymology with the c-di-GMP-bound BcsA-B crystals. Because crystallized BcsA-B is catalytically a...

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The transporter associated with antigen processing: a key player in adaptive immunity

Cited by 64 publications

References 121 publications

Oncolytic herpes simplex virus interactions with the host immune system

Oncolytic herpes simplex virus interactions with the host immune system

Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands

Structural Studies of Biopolymer Membrane Transport

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