Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation

Wenger, Till; Terawaki, Seigo; Camosseto, Voahirana; Abdel-Rassoul, Ronza; Mies, Anna; Catalan, Nadia; Cláudio, Nuno; Clavarino, Giovanna; Gassart, Aude De; Rigotti, Francesca; Gatti, Evelina; Pierre, Philippe

doi:10.4161/auto.18806

Cited by 58 publications

(57 citation statements)

References 56 publications

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“…25 DALIS function as a reservoir for MHC I antigens and are putative substrates of autophagy. 26 Here, we detected ubiquitinated aggregates in the primary DC subsets using an antibody that recognizes poly-and mono-ubiquitinated proteins, but not free ubiquitin. Few ubiquitinated aggregates were present in either the immature DC subsets, or activated CD8 ¡ DC as measured by IFC.…”

Section: Resultsmentioning

confidence: 81%

Differential use of autophagy by primary dendritic cells specialized in cross-presentation

et al. 2015

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Abbreviations: 3-MA, 3-methyladenine; Atg7-DC CKO, Atg7 DC conditional knockout; BafA, bafilomycin A 1 ; CD, cluster of differentiation; CTL, cytotoxic T lymphocyte; DC, dendritic cell; DALIS, dendritic cell aggresome-like inducible structures; green fluorescent protein, GFP; IFC imaging flow cytometry; LAP, LC3 associated phagocytosis; LC3B, microtubule-associated protein 1 light chain 3 b; MHC II, major histocompatibility complex class II; MHC I, major histocompatibility complex class I; OVA, ovalbumin; OT-I, OVA-specific CD8 C T cell; OT-II, OVA-specific CD4 C T cell; SIM, structured illumination microscopy.Antigen-presenting cells survey their environment and present captured antigens bound to major histocompatibility complex (MHC) molecules. Formation of MHC-antigen complexes occurs in specialized compartments where multiple protein trafficking routes, still incompletely understood, converge. Autophagy is a route that enables the presentation of cytosolic antigen by MHC class II molecules. Some reports also implicate autophagy in the presentation of extracellular, endocytosed antigen by MHC class I molecules, a pathway termed "cross-presentation." The role of autophagy in cross-presentation is controversial. This may be due to studies using different types of antigen presenting cells for which the use of autophagy is not well defined. Here we report that active use of autophagy is evident only in DC subtypes specialized in cross-presentation. However, the contribution of autophagy to cross-presentation varied depending on the form of antigen: it was negligible in the case of cell-associated antigen or antigen delivered via receptor-mediated endocytosis, but more prominent when the antigen was a soluble protein. These findings highlight the differential use of autophagy and its machinery by primary cells equipped with specific immune function, and prompt careful reassessment of the participation of this endocytic pathway in antigen cross-presentation.

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Section: Resultsmentioning

confidence: 81%

Differential use of autophagy by primary dendritic cells specialized in cross-presentation

et al. 2015

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“…It involves de novo formation of a double membrane that sequesters a portion of the cytoplasm in an autophagosome, which then matures into a lytic vesicle (21). As for the ubiquitin/proteasome system, autophagy participates in quality control of protein aggregates and thus affects Ag presentation (22). In particular, defective ribosomal products (DRiPs), which constitute a source of Ag for MHC-I-restricted presentation, form aggregates that are degraded by both the ubiquitin/proteasome system and autophagy (22).…”

Section: A Ccumulating Evidence Suggests That Hiv-specific (Hs) Cd4mentioning

confidence: 99%

“…As for the ubiquitin/proteasome system, autophagy participates in quality control of protein aggregates and thus affects Ag presentation (22). In particular, defective ribosomal products (DRiPs), which constitute a source of Ag for MHC-I-restricted presentation, form aggregates that are degraded by both the ubiquitin/proteasome system and autophagy (22). Autophagy has been shown to contribute to presentation of HSV-1 and CMV Ags by MHC-I molecules (23,24).…”

Section: A Ccumulating Evidence Suggests That Hiv-specific (Hs) Cd4mentioning

confidence: 99%

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

Coulon

Richetta

Rouers

et al. 2016

The Journal of Immunology

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It is widely assumed that CD4+ T cells recognize antigenic peptides (epitopes) derived solely from incoming, exogenous, viral particles or proteins. However, alternative sources of MHC class II (MHC-II)–restricted Ags have been described, in particular epitopes derived from newly synthesized proteins (so-called endogenous). In this study, we show that HIV-infected dendritic cells (DC) present MHC-II–restricted endogenous viral Ags to HIV-specific (HS) CD4+ T cells. This endogenous pathway functions independently of the exogenous route for HIV Ag presentation and offers a distinct possibility for the immune system to activate HS CD4+ T cells. We examined the implication of autophagy, which plays a crucial role in endogenous viral Ag presentation and thymic selection of CD4+ T cells, in HIV endogenous presentation. We show that infected DC do not use autophagy to process MHC-II–restricted HIV Ags. This is unlikely to correspond to a viral escape from autophagic degradation, as infecting DC with Nef- or Env-deficient HIV strains did not impact HS T cell activation. However, we demonstrate that, in DC, specific targeting of HIV Ags to autophagosomes using a microtubule-associated protein L chain 3 (LC3) fusion protein effectively enhances and broadens HS CD4+ T cell responses, thus favoring an endogenous MHC-II–restricted presentation. In summary, in DC, multiple endogenous presentation pathways lead to the activation of HS CD4+ T cell responses. These findings will help in designing novel strategies to activate HS CD4+ T cells that are required for CTL activation/maintenance and B cell maturation.

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“…Intracellular antigen presentation via MHC class I molecules is also regulated by the autophagy machinery, because autophagy‐related proteins enhance MHC class I internalization for degradation and thereby diminish antigen display on the cell surface 268. Indeed, in vivo studies have primarily found enhanced CD8 + T cell responses in mice with defective autophagy in antigen‐presenting cells268, 269, 270 A potential mechanism leading to such increased CD8 + T cell expansions is that, in the absence of autophagy, more substrate becomes available for canonical MHC class I loading271 or by decreased endocytosis and degradation of cell surface MHC class I molecules 268. Thus, defective autophagy in skeletal muscle fibers could drive increased MHC class I expression and CD8 + T cell accumulation.…”

Section: Degenerative Pathomechanisms In Ibmmentioning

confidence: 99%

“…The resulting peptides are fed into the MHC class I presenting pathway and will be surveilled by CD8 + T cells 287. Upon impairment of autophagy in HeLa cells, its substrates accumulate in p62/SQSTM1‐positive aggresome‐like induced structures and are fed into the proteasomal pathway with subsequent presentation via MHC class I 271. Differential activity of autophagy might, therefore, shape the peptide pool presented on MHC class I and it is tempting to speculate that impairment of this control mechanism in IBM muscle abets invasion of myoaggressive immune cells.…”

Section: Degenerative Pathomechanisms In Ibmmentioning

confidence: 99%

Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.

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Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation

Cited by 58 publications

References 56 publications

Differential use of autophagy by primary dendritic cells specialized in cross-presentation

Differential use of autophagy by primary dendritic cells specialized in cross-presentation

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

Immune and myodegenerative pathomechanisms in inclusion body myositis

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