Figure - available from: Frontiers in Immunology
This content is subject to copyright.
Macro-, micro-, and chaperone-mediated autophagy. Macroautophagy can engulf cytoplasmic material to form autophagosomes, which then can fuse with multivesicular bodies (MVBs) or directly with lysosomes. Cytosolic KFERQ-like signal peptide containing proteins may get transported in an HSC70 dependent fashion into MVBs by microautophagy, or via docking to Lamp2a and intravesicular HSP70 assisted import into lysosomes. The MVB content might also get degraded after fusion with lysosomes.
Source publication
T cells recognize antigen fragments, presented to them by MHC molecules. It lies in the interest of the immune system to display a maximal diversity of these peptides and utilize all catabolic processes to generate them. Macroautophagy, a pathway that delivers cytoplasmic constituents for lysosomal degradation is no exception. In recent years, it h...
Similar publications
Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Micro...
Citations
... As mentioned above, following viral/bacterial infections, APC such as macrophages and dendritic cells process viral/bacterial antigens and subsequently APC present the processed antigen to T cells by MHC molecules. This antigen processing and presentation by MHC molecules to T-cells is in part, an autophagy dependent process [46,47]. Autophagy links both the innate and adaptive immune systems, which includes thymic selection, antigen presentation, maintenance of lymphocyte homeostasis and survival, and regulation of cytokine production during bacterial/viral infections [48]. ...
The recent global pandemic due to COVID-19 is caused by a type of coronavirus, SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Despite rigorous efforts worldwide to control the spread and human to human transmission of this virus, incidence and death due to COVID-19 continue to rise. Several drugs have been tested for treatment of COVID-19, including hydroxychloroquine. While a number of studies have shown that hydroxychloroquine can prolong QT interval, potentially increasing risk of ventricular arrhythmias and Torsade de Pointes, its effects on immune cell function have not been extensively examined. In the current review, an overview of coronaviruses, viral entry and pathogenicity, immunity upon coronavirus infection, and current therapy options for COVID-19 are briefly discussed. Further based on preclinical studies, we provide evidences that i) hydroxychloroquine impairs autophagy, which leads to accumulation of damaged/oxidized cytoplasmic constituents and interferes with cellular homeostasis, ii) this impaired autophagy in part reduces antigen processing and presentation to immune cells and iii) inhibition of endosome-lysosome system acidification by hydroxychloroquine not only impairs the phagocytosis process, but also potentially alters pulmonary surfactant in the lungs. Therefore, it is likely that hydroxychloroquine treatment may in fact impair host immunity in response to SARS-CoV-2, especially in elderly patients or those with co-morbidities. Further, this review provides a rationale for developing and selecting antiviral drugs and includes a brief review of traditional strategies combined with new drugs to combat COVID-19.
... For example, LC3s regulate a specific phagocytosis process called LC3-associated phagocytosis (LAP), which induces transmembrane receptor uptake, e.g., TLR (toll like receptors), TRIM4 (tripartite motif containing 4) or CLEC7A/Dectin-1, from the plasma membrane to the lysosome to induce their degradation [23]. The LAP mechanism has been described to be implicated in the antigen presentation on major histocompatibility complex (MHC) and, therefore, leads to immune system activation [24]. LAP has only been described for LC3s, and no study, to our knowledge, implicates the involvement of GABARAPs in this process. ...
... Firstly, GABARAP appeared to be necessary to develop an efficient antitumor immune response through its implication in cytokine secretion [133]. Then, LC3s have been shown to be important for efficient extracellular antigen processing, presentation, and induction of T-cell anti-tumor response by dendritic cells in mice [24,134]. The role of the LC3s during antigen presentation involves the LAP, a mechanism implicated in tumor growth, which is only described for the LC3 proteins but not for GABARAPs. ...
The Atg8-family proteins are subdivided into two subfamilies: the GABARAP and LC3 subfamilies. These proteins, which are major players of the autophagy pathway, present a conserved glycine in their C-terminus necessary for their association to the autophagosome membrane. This family of proteins present multiple roles from autophagy induction to autophagosome-lysosome fusion and have been described to play a role during cancer progression. Indeed, GABARAPs are described to be downregulated in cancers, and high expression has been linked to a good prognosis. Regarding LC3 s, their expression does not correlate to a particular tumor type or stage. The involvement of Atg8-family proteins during cancer, therefore, remains unclear, and it appears that their anti-tumor role may be associated with their implication in selective protein degradation by autophagy but might also be independent, in some cases, of their conjugation to autophagosomes. In this review, we will then focus on the involvement of GABARAP and LC3 subfamilies during autophagy and cancer and highlight the similarities but also the differences of action of each subfamily member.
Abbreviations: AIM: Atg8-interacting motif; AMPK: adenosine monophosphate-associated protein kinase; ATG: autophagy-related; BECN1: beclin 1; BIRC6/BRUCE: baculoviral IAP repeat containing 6; BNIP3L/NIX: BCL2 interacting protein 3 like; GABARAP: GABA type A receptor-associated protein; GABARAPL1/2: GABA type A receptor associated protein like 1/2; GABRA/GABAA: gamma-aminobutyric acid type A receptor subunit; LAP: LC3-associated phagocytosis; LMNB1: lamin B1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PI4K2A/PI4KIIα: phosphatidylinositol 4-kinase type 2 alpha; PLEKHM1: plecktrin homology and RUN domain containing M1; PtdIns3K-C1: class III phosphatidylinositol 3-kinase complex 1; SQSTM1: sequestosome 1; ULK1: unc51-like autophagy activating kinase 1.
... (Dongre et al., 2001;Rudensky et al., 1991;Zhou and Blum, 2004). L'un des mécanismes impliqué dans cette voie de présentation non classique est l'autophagie, en particulier la macroautophagie (Crotzer and Blum, 2010;Münz, 2011Münz, , 2012Nimmerjahn et al., 2003). Cependant, d'autres voies ont pu être identifiées dans cette présentation non classique aux molécules de CMH-II, comme celle passant par la voie du protéasome, des protéines TAP et des protéines chaperonnes (Li et al., 2005;Mukherjee et al., 2001;Tewari et al., 2005), ou passant par des transferts intercellulaires de molécules de CMH-II par trogocytose ou par l'intermédiaire d'exosomes (Nakayama, 2015). ...
La théorie actuelle de l'immunosurveillance des cancers établit l'existence d'un système dynamique d'interaction entre le système immunitaire et les cellules tumorales. Plusieurs expériences majeures ont démontré l'importance du système immunitaire et en particulier des lymphocytes T dans la surveillance des cancers et dans l'efficacité des thérapies antitumorales. Certains traitements utilisés contre le cancer peuvent en effet stimuler ou inhiber la réponse immunitaire antitumorale. En plus de leur effet cytotoxique sur les cellules cancéreuses ces médicaments, tel que le Sorafenib, peuvent inhiber des cellules immunosuppressives telles que les Treg et les MDSC. D'autres chimiothérapies, telle que l'Oxaliplatine, peuvent induire une mort cellulaire immunogène nécessaire à leur efficacité clinique. L'Oxaliplatine est également connue pour ajouter des groupements alkyles sur les bases puriques de l'ADN à l'origine de mutations. Parallèlement, la caractérisation de nombreuses mutations immunogènes a été menée au cours des dernières années sans que le rôle des traitements dans l'apparition de celle-ci n'ait été recherché. Les mutations spécifiques des agents alkylants correspondent à une modification des bases AG, GG et de la base en S' de groupe AG ou GG. Ces mutations permettraient de diversifier le répertoire antigénique en créant des néoantigènes reconnus par les lymphocytes T. L'objectif principal de ce travail a été d'identifier de nouveaux épitopes immunogènes issus d'antigènes de tumeurs en utilisant une stratégie d'immunologie inverse. La première partie a permis l'identification de trois néoépitopes immunogènes restreints par le CMH-II et potentiellement impliqués dans la rémission complète d'un patient atteint d'un hépatocarcinome métastatique traité par Sorafenib. L'immunogénicité de ces trois néoépitopes issus des protéines HELZ2, MLL2 et IL-1β mutées a été validée après stimulation in vitro des lymphocytes T du patient. La seconde partie, portant sur l'identification de néoantigènes induits par Oxaliplatine a permis de poursuivre la caractérisation des mutations chimioinduites et d’identifier 26 néoépitopes potentiellement présentés par les CMH de classe I.Ces travaux renforcent le lien entre système immunitaire et l’efficacité des chimiothérapies. Ils suggèrent pour la première fois que les chimiothérapies pourraient augmenter l’immunogénicité des tumeurs, en augmentant le répertoire des néoantigènes.
... Autophagy also affects cancer metastasis, which depends on the phase. It promotes the formation of metastases in advanced stages of the disease by increasing the survival of metastatic cells in the absence of extracellular matrix and by allowing the spread of cancer cells to distant organs [18] [19] [20] [21]. It follows that autophagy can inhibit formation of tumors or enhance it and protect cancer cells from death [22]. ...
Background: Autophagocytosis is a biological process involving the controlled distribution of cell fragments and organelles in order to obtain an additional source of energy. LAMP3 (lysosome-associated membrane protein 3) is a heavily glycosylated integral membrane protein located mainly in the lysosomal membrane. Recent studies have shown that it participates in tumor metastasis and drug resistance. Its main role is contribution to tumor cells proliferation, migration and invasion. The aim of this study was to determine changes in transcriptional activity of LAMP3 at various stages of colorectal cancer. In addition, an attempt was made to select miRNAs potentially regulating LAMP3 expression using bioinformatic databases. Methods: The study was conducted on healthy colon samples and colon cancer samples in four stages. Molecular analysis included the extraction of total RNA, purification of the obtained extracts, expression profile analysis using oligonucleotide microarray technique and in silico determination of miRNAs potentially regulating the LAMP3 expression. Results: The level of LAMP3 expression is higher in colorectal adenocarcinoma cells than in non-cancerous cells and depends on the stage of the disease. Conclusions: LAMP3 may promote cancer progression, metastasis and cause the resistance to treatment.
Keywords:Autophagy, Colorectal Cancer, LAMP3, Microarrays, miRNA
... Induction of cellular autophagy process during virus infection has been shown to stimulate the innate immune response, including toll-like receptors (TLR) signaling and antigen presentation in complex with major histocompatibility complex (MHC)-1 and MHC-II molecules [149][150][151][152]. HCV induced autophagy has been found to play a major role in evading host microbial defense mechanisms at the level of innate and adaptive immune response [153]. ...
Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms by which HCV infection leads to chronic liver disease and HCC are not well understood. The infection cycle of HCV is initiated by the attachment and entry of virus particles into a hepatocyte. Replication of the HCV genome inside hepatocytes leads to accumulation of large amounts of viral proteins and RNA replication intermediates in the endoplasmic reticulum (ER), resulting in production of thousands of new virus particles. HCV-infected hepatocytes mount a substantial stress response. How the infected hepatocyte integrates the viral-induced stress response with chronic infection is unknown. The unfolded protein response (UPR), an ER-associated cellular transcriptional response, is activated in HCV infected hepatocytes. Over the past several years, research performed by a number of laboratories, including ours, has shown that HCV induced UPR robustly activates autophagy to sustain viral replication in the infected hepatocyte. Induction of the cellular autophagy response is required to improve survival of infected cells by inhibition of cellular apoptosis. The autophagy response also inhibits the cellular innate antiviral program that usually inhibits HCV replication. In this review, we discuss the physiological implications of the HCV-induced chronic ER-stress response in the liver disease progression.
... PKR is a key player in the antiviral action of interferon and many viruses express proteins that antagonize the PKR signaling [290]. In herpesvirus-mediated pathogenesis, autophagy plays a role in antiviral cell defense either by clearing intracellular viruses or by activating antigen presentation [291]. Therefore, it is hypothesized that herpesvirus evolved intricate mechanisms to antagonize autophagy. ...
Worldwide, one fifth of cancers in the population are associated with viral infections. Among them, gammaherpesvirus, specifically HHV4 (EBV) and HHV8 (KSHV), are two oncogenic viral agents associated with a large number of human malignancies. In this review, we summarize the current understanding of the molecular mechanisms related to EBV and KSHV infection and their ability to induce cellular transformation. We describe their strategies for manipulating major cellular systems through the utilization of cell cycle, apoptosis, immune modulation, epigenetic modification, and altered signal transduction pathways, including NF-kB, Notch, Wnt, MAPK, TLR, etc. We also discuss the important EBV latent antigens, namely EBNA1, EBNA2, EBNA3's and LMP's, which are important for targeting these major cellular pathways. KSHV infection progresses through the engagement of the activities of the major latent proteins LANA, v-FLIP and v-Cyclin, and the lytic replication and transcription activator (RTA). This review is a current, comprehensive approach that describes an in-depth understanding of gammaherpes viral encoded gene manipulation of the host system through targeting important biological processes in viral-associated cancers.
... It has been described that autophagy can be directly activated by PAMP-dependent stimulation of TLRs resulting in the induction of an interferon (IFN)-response [159,160] . Furthermore, the autolysosomal degradation of viral particles or proteins leads to MHC class Ⅱ-dependent antigen presentation and subsequent activation of the adaptive immune response [161] . Many viruses have developed strategies to escape the innate immune response. ...
Autophagy is a highly-regulated, conserved cellular process for the degradation of intracellular components in lysosomes to maintain the energetic balance of the cell. It is a pro-survival mechanism that plays an important role during development, differentiation, apoptosis, ageing and innate and adaptive immune response. Besides, autophagy has been described to be involved in the development of various human diseases, e.g., chronic liver diseases and the development of hepatocellular carcinoma. The hepatitis C virus (HCV) is a major cause of chronic liver diseases. It has recently been described that HCV, like other RNA viruses, hijacks the autophagic machinery to improve its replication. However, the mechanisms underlying its activation are conflicting. HCV replication and assembly occurs at the so-called membranous web that consists of lipid droplets and rearranged endoplasmic reticulum-derived membranes including single-, double- and multi-membrane vesicles. The double-membrane vesicles have been identified to contain NS3, NS5A, viral RNA and the autophagosomal marker microtubule-associated protein 1 light chain 3, corroborating the involvement of the autophagic pathway in the HCV life-cycle. In this review, we will highlight the crosstalk of the autophagosomal compartment with different steps of the HCV life-cycle and address its implications on favoring the survival of infected hepatocytes.
... Otro estudio, reseña que la presentación-cruzada de ovalbúmina y el antígeno de diferenciación de melanocitos gp100 sobre las líneas celulares de melanoma y epitelial fue regulado negativamente por la presencia de un ARN de interferencia sobre los genes Atg6 y Atg12 (34,50,52). A pesar de los resultados obtenidos, se requieren más estudios que permitan establecer la importancia de la macroautofagia en la presentación-cruzada antigénica (51,52,53). ...
... Otro estudio, reseña que la presentación-cruzada de ovalbúmina y el antígeno de diferenciación de melanocitos gp100 sobre las líneas celulares de melanoma y epitelial fue regulado negativamente por la presencia de un ARN de interferencia sobre los genes Atg6 y Atg12 (34,50,52). A pesar de los resultados obtenidos, se requieren más estudios que permitan establecer la importancia de la macroautofagia en la presentación-cruzada antigénica (51,52,53). ...
Autophagy is a complex process in which cell homeostasis of proteins, organelles, exocitic and endocitic vacuoles are controlled. There is a direct link between autophagy and cell death with antigen processing, generation of inflammatory response and immune response. In different diseases, deficiencies in autophagy have been reported. It has been proposed that in early stages of cancer, autophagy is capable of inducing cell death; however, in agresive tumors and metastasis, the process is responsible for pharmacologic resistance and tumor survival. More research has to be done in order to allow us to understand the process and generate therapeutic options in different pathologies important for the human being.
... The role of autophagy is not limited to the innate immune response, but also plays a major role in the adaptive immune response by processing and delivering antigens for presentation in complex with MHC-I and MHC-II molecules [63] (Figure 3). Typically, MHC-I molecules present endogenous antigens that are degraded by the proteasome and transported into the ER, where they are loaded onto MHC-I molecules. ...
Viruses have played an important role in human evolution and have evolved diverse strategies to co-exist with their hosts. As obligate intracellular pathogens, viruses exploit and manipulate different host cell processes, including cellular trafficking, metabolism and immunity-related functions, for their own survival. In this article, we review evidence for how autophagy, a highly conserved cellular degradative pathway, serves either as an antiviral defense mechanism or, alternatively, as a pro-viral process during virus infection. Furthermore, we highlight recent reports concerning the role of selective autophagy in virus infection and how viruses manipulate autophagy to evade lysosomal capture and degradation.
