Antigen Presentation and the Ubiquitin‐Proteasome System in Host–Pathogen Interactions

Abstract

Relatively small genomes and high replication rates allow viruses and bacteria to accumulate mutations. This continuously presents the host immune system with new challenges. On the other side of the trenches, an increasingly well-adjusted host immune response, shaped by coevolutionary history, makes a pathogen's life a rather complicated endeavor. It is, therefore, no surprise that pathogens either escape detection or modulate the host immune response, often by redirecting normal cellular pathways to their advantage. For the purpose of this chapter, we focus mainly on the manipulation of the class I and class II major histocompatibility complex (MHC) antigen presentation pathways and the ubiquitin (Ub)-proteasome system by both viral and bacterial pathogens. First, we describe the general features of antigen presentation pathways and the Ub-proteasome system and then address how they are manipulated by pathogens. We discuss the many human cytomegalovirus (HCMV)-encoded immunomodulatory genes that interfere with antigen presentation (immunoevasins) and focus on the HCMV immunoevasins US2 and US11, which induce the degradation of class I MHC heavy chains by the proteasome by catalyzing their export from the endoplasmic reticulum (ER)-membrane into the cytosol, a process termed ER dislocation. US2- and US11-mediated subversion of ER dislocation ensures proteasomal degradation of class I MHC molecules and presumably allows HCMV to avoid recognition by cytotoxic T cells, whilst providing insight into general aspects of ER-associated degradation (ERAD) which is used by eukaryotic cells to purge their ER of defective proteins. We discuss the similarities and differences between the distinct pathways co-opted by US2 and US11 for dislocation and degradation of human class I MHC molecules and also a putatively distinct pathway utilized by the murine herpes virus (MHV)-68 mK3 immunoevasin for ER dislocation of murine class I MHC. We speculate on the implications of the three pathogen-exploited dislocation pathways to cellular ER quality control. Moreover, we discuss the ubiquitin (Ub)-proteasome system and its position at the core of antigen presentation as proteolysis and intracellular trafficking rely heavily on Ub-dependent processes. We add a few examples of manipulation of the Ub-proteasome system by pathogens in the context of the immune system and such diverse aspects of the host-pathogen relationship as virus budding, bacterial chromosome integration, and programmed cell death, to name a few. Finally, we speculate on newly found pathogen-encoded deubiquitinating enzymes (DUBs) and their putative roles in modulation of host-pathogen interactions.

HIV-1 Nef-induced Down-Regulation of MHC Class I Requires AP-1 and Clathrin but Not PACS-1 and Is Impeded by AP-2

“…The mechanisms that viruses use to down-regulate MHC-I are as varied as the viruses themselves, and include blocking the transcription of MHC-I genes, preventing newly synthesized MHC-I from leaving the ER, and ubiquitinating MHC-I at the plasma membrane so that it is endocytosed and degraded in lysosomes (Ploegh, 1998;Hewitt et al, 2002;Loureiro and Ploegh, 2006). HIV-1 is one of the most intensively studied of all viruses, and a role for HIV-1 Nef in the down-regulation of MHC-I was first demonstrated Ͼ10 years ago (Schwartz et al, 1996).…”

Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules

“…HCMV has evolved strategies to utilize existing cellular processes to escape immune detection (Loureiro & Ploegh, 2006). The current data extend the paradigm that HCMV coopts host machinery to include the use of ER chaperone complexes to modulate class I antigen presentation.…”

How Viruses Use the Endoplasmic Reticulum for Entry, Replication, and Assembly

“…CD4 down-regulation leads to a series of events including disruption of T cell activation (Lanzavecchia et al 1988), ultimately contributing to robust HIV infection. As there are many reviews on how viruses use the ER to thwart the host immune system (Loureiro and Ploegh 2006;Lindwasser et al 2007;Hansen and Bouvier 2009;Jackson et al 2011), this topic will not be covered extensively in this article. Nonetheless, it unveils another aspect of the ER function that viruses hijack to maintain infection.…”