Autophagy in MHC Class II Presentation of Endogenous Antigens

Gannagé, Monique; Münz, Christian

doi:10.1007/978-3-642-00302-8_6

Cited by 34 publications

(33 citation statements)

References 79 publications

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“…Autophagy assists not only in the direct elimination of pathogens by hydrolytic degradation but also in antigen processing in antigen-presenting cells such as macrophage and dendritic cells (DC) for presentation by major histocompatibility complex (MHC) I and II (11). Moreover, autophagy plays important roles in T lymphocyte homeostasis (44).…”

Section: Discussionmentioning

confidence: 99%

Dysfunction of Autophagy Participates in Vacuole Formation and Cell Death in Cells Replicating Hepatitis C Virus

Taguwa¹,

Kambara²,

Fujita

et al. 2011

J Virol

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Hepatitis C virus (HCV) is a major cause of chronic liver diseases. A high risk of chronicity is the major concern of HCV infection, since chronic HCV infection often leads to liver cirrhosis and hepatocellular carcinoma. Infection with the HCV genotype 1 in particular is considered a clinical risk factor for the development of hepatocellular carcinoma, although the molecular mechanisms of the pathogenesis are largely unknown. Autophagy is involved in the degradation of cellular organelles and the elimination of invasive microorganisms. In addition, disruption of autophagy often leads to several protein deposition diseases. Although recent reports suggest that HCV exploits the autophagy pathway for viral propagation, the biological significance of the autophagy to the life cycle of HCV is still uncertain. Here, we show that replication of HCV RNA induces autophagy to inhibit cell death. Cells harboring an HCV replicon RNA of genotype 1b strain Con1 but not of genotype 2a strain JFH1 exhibited an incomplete acidification of the autolysosome due to a lysosomal defect, leading to the enhanced secretion of immature cathepsin B. The suppression of autophagy in the Con1 HCV replicon cells induced severe cytoplasmic vacuolation and cell death. These results suggest that HCV harnesses autophagy to circumvent the harmful vacuole formation and to maintain a persistent infection. These findings reveal a unique survival strategy of HCV and provide new insights into the genotype-specific pathogenicity of HCV.Hepatitis C virus (HCV) is a major causative agent of bloodborne hepatitis and currently infects at least 180 million people worldwide (58). The majority of individuals infected with HCV develop chronic hepatitis, which eventually leads to liver cirrhosis and hepatocellular carcinoma (25,48). In addition, HCV infection is known to induce extrahepatic diseases such as type 2 diabetes and malignant lymphoma (20). It is believed that the frequency of development of these diseases varies among viral genotypes (14, 51). However, the precise mechanism of the genotype-dependent outcome of HCV-related diseases has not yet been elucidated. Despite HCV's status as a major public health problem, the current therapy with pegylated interferon and ribavirin is effective in only around 50% of patients with genotype 1, which is the most common genotype worldwide, and no effective vaccines for HCV are available (35, 52). Although recently approved protease inhibitors for HCV exhibited a potent antiviral efficacy in patients with genotype 1 (36, 43), the emergence of drug-resistant mutants is a growing problem (16). Therefore, it is important to clarify the life cycle and pathogenesis of HCV for the development of more potent remedies for chronic hepatitis C.HCV belongs to the genus Hepacivirus of the family Flaviviridae and possesses a single positive-stranded RNA genome with a nucleotide length of 9.6 kb, which encodes a single polyprotein consisting of approximately 3,000 amino acids (40). The precursor polyprotein is processed by host...

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Section: Discussionmentioning

confidence: 99%

Dysfunction of Autophagy Participates in Vacuole Formation and Cell Death in Cells Replicating Hepatitis C Virus

Taguwa¹,

Kambara²,

Fujita

et al. 2011

J Virol

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“…With recent work highlighting the potential for macroautophagy to orchestrate the endogenous MHC class II-restricted presentation of individual antigens (16,35,44,45,50,60), our goal was to determine the role in the CD4 ϩ T cell response to a complex pathogen, specifically influenza virus. We focused on this virus due to our previous elucidation of a proteasome-dependent endogenous pathway that is responsible for a substantial portion of the class II-restricted response to influenza virus infection (66).…”

Section: Discussionmentioning

confidence: 99%

Functional Macroautophagy Induction by Influenza A Virus without a Contribution to Major Histocompatibility Complex Class II-Restricted Presentation

Comber

Robinson

Siciliano

et al. 2011

J Virol

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Major histocompatibility complex (MHC) class II-presented peptides can be derived from both exogenous (extracellular) and endogenous (biosynthesized) sources of antigen. Although several endogenous antigenprocessing pathways have been reported, little is known about their relative contributions to global CD4؉ T cell responses against complex antigens. Using influenza virus for this purpose, we assessed the role of macroautophagy, a process in which cytosolic proteins are delivered to the lysosome by de novo vesicle formation and membrane fusion. Influenza infection triggered productive macroautophagy, and autophagy-dependent presentation was readily observed with model antigens that naturally traffic to the autophagosome. Furthermore, treatments that enhance or inhibit macroautophagy modulated the level of presentation from these model antigens. However, validated enzyme-linked immunospot (ELISpot) assays of influenza-specific CD4 ؉ T cells from infected mice using a variety of antigen-presenting cells, including primary dendritic cells, revealed no detectable macroautophagy-dependent component. In contrast, the contribution of proteasome-dependent endogenous antigen processing to the global influenza CD4؉ response was readily appreciated. The contribution of macroautophagy to the MHC class II-restricted response may vary depending upon the pathogen. The activation of CD4ϩ T cells depends upon their recognition of peptides (epitopes) associated with major histo compatibility class (MHC) class II molecules. Conventionally, peptide generation involves the degradation of exogenous (extracellular) antigens in the endosomal network by multiple mechanisms, including unfolding, reduction, and proteolytic degradation. It is now clear that epitopes derived from endogenous antigens (synthesized by the cell) also can be presented on MHC class II molecules (12,22,24,38,49,50,60,66). Indeed, endogenous antigen expression appears to be an absolute requirement for the presentation of some epitopes. For example, the UV inactivation of A/PR8/34 influenza virus (PR8) or treatment of infected antigen-presenting cells (APCs) with protein synthesis inhibitors prevents the presentation of the NA79 epitope (12). Similar observations have been made for an epitope derived from influenza matrix protein 1 (24) and an epitope derived from the MHC class I H2-L d molecule (39).Numerous studies now have demonstrated that endogenous antigens can gain access to MHC class II loading compartments via a variety of intracellular pathways (4,38,49,57,66,67). Perhaps the most straightforward route is autophagy, in which cytosolic proteins are delivered to the lysosome via several different mechanisms. Chaperone-mediated autophagy results in the delivery of cytosolic proteins directly to the lysosome based upon the recognition of a KFERQ pentapeptide motif within the target protein, and it was shown to be responsible for the presentation of an epitope derived from glutamate decarboxylase (72). Although 30% of cytosolic proteins contain this motif (70)...

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“…[5][6][7][8] Autophagy also plays a fundamental role in innate and adaptive immunity, [9][10][11][12][13] contributing to the clearance of intracellular pathogens, either directly by xenophagy [13][14][15] or being involved in MHC II-restricted microbial antigen presentation. 16 Due to the pivotal role of autophagy in the immune response, intracellular pathogens such as viruses have evolved several strategies to interfere with it, in order to survive in the infected host. [17][18][19] The 2 human gamma-herpesviruses Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus (KSHV) 20 represent examples of viruses that affect autophagy in different fashions.…”

Section: Introductionmentioning

confidence: 99%

KSHV reduces autophagy in THP-1 cells and in differentiating monocytes by decreasing CAST/calpastatin and ATG5 expression

et al. 2016

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We have previously shown that Kaposi sarcoma-associated herpesvirus (KSHV) impairs monocyte differentiation into dendritic cells (DCs). Macroautophagy/autophagy has been reported to be essential in such a differentiating process. Here we extended these studies and found that the impairment of DC formation by KSHV occurs through autophagy inhibition. KSHV indeed reduces CAST (calpastatin) and consequently decreases ATG5 expression in both THP-1 monocytoid cells and primary monocytes. We unveiled a new mechanism put in place by KSHV to escape from immune control. The discovery of viral immune suppressive strategies that contribute to the onset and progression of viral-associated malignancies is of fundamental importance for finding new therapeutic approaches against them.

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Autophagy in MHC Class II Presentation of Endogenous Antigens

Cited by 34 publications

References 79 publications

Dysfunction of Autophagy Participates in Vacuole Formation and Cell Death in Cells Replicating Hepatitis C Virus

Dysfunction of Autophagy Participates in Vacuole Formation and Cell Death in Cells Replicating Hepatitis C Virus

Functional Macroautophagy Induction by Influenza A Virus without a Contribution to Major Histocompatibility Complex Class II-Restricted Presentation

KSHV reduces autophagy in THP-1 cells and in differentiating monocytes by decreasing CAST/calpastatin and ATG5 expression

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