Dendritic cell aggresome-like induced structures are dedicated areas for ubiquitination and storage of newly synthesized defective proteins

Lelouard, Hugues; Ferrand, Vincent; Marguet, Didier; Bania, Jacek; Camosseto, Voahirana; David, Alexandre; Gatti, Evelina; Pierre, Philippe

doi:10.1083/jcb.200312073

Cited by 138 publications

(196 citation statements)

References 30 publications

Supporting

Mentioning

184

Contrasting

Order By: Relevance

“…2G), supporting previous observations of DALIS structure. 28 We extended our analysis to mouse primary DC that undergo activation naturally in vivo. To do this, we analyzed DC isolated from lymph nodes.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In addition to the aforementioned exogenous route of partially proteasome-dependent antigen processing in DCs, MHC-I antigen processing of endogenous proteins from defective ribosomal products (DRiPs) [26,27] is tightly coordinated within DC maturation as well: DRiPs transiently accumulate as polyubiquitinylated conglomerates in DALISs during DC maturation [ 28,29]. To study this process in the murine model of ongoing enterovirus myocarditis, poly-ubiquitinylation and DALIS formation were assessed in DCs from both C57BL/6 and A.BY/SnJ mice.…”

Section: Ubiquitinylation/dalis Accumulation/isgylation In Dcs In Cvbmentioning

confidence: 99%

“…20S and 26S proteasome activity were not affected within DC maturation in both hosts (data not shown). DALISs are dedicated areas of antigen storage, allowing for the prioritized degradation of proteins during infection [28,29] until the secretion of proinflammatory cytokines and expression of co-stimulatory molecules has been induced in mature DCs [29]. Impaired degradation of DALISs in A.BY/SnJ mice may point to a limitation of the endogenous DRiP supply for MHC-I restricted antigen processing due to prolonged storage of DRiPs in DALISs.…”

Section: Ubiquitinylation/dalis Accumulation/isgylation In Dcs In Cvbmentioning

confidence: 99%

Antigen‐presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis

et al. 2011

View full text Add to dashboard Cite

Coxsackievirus B3 (CVB3)‐infection is a frequent cause of acute myocarditis, which may result in chronic myocarditis and virus persistence. Investigation of the initial immune responses to CVB3 may shed light on the mechanisms that contribute to ongoing disease. DCs, as key professional APCs, were investigated in two MHC‐matched hosts: while C57BL/6 mice are resistant to chronic CVB3‐myocarditis, the A.BY/SnJ mouse strain exhibits susceptibility. DC maturation and activation were critically impaired in A.BY/SnJ mice, as reflected by the failure of DCs to induce co‐stimulatory molecules and cytokine/chemokine responses. MHC class I‐restricted antigen presentation via the cross‐presentation pathway was also affected in DCs from A.BY/SnJ mice. DC maturation involves the accumulation of DC aggresome‐like induced structures (DALISs) and the transient storage of defective ribosomal products (DRiPs). DCs from A.BY/SnJ mice showed permanent DALIS accumulation; the detection of poly‐ubiquitinylated CVB3 proteins in these DALISs suggested a limitation in the MHC class I antigenic supply in this host. In conclusion, ongoing chronic disease in A.BY/SnJ mice due to a failure to clear the virus may be attributed to defects in DC maturation/activation and DC MHC class I antigen processing.

show abstract

“…ALIS refers to DALIS (dendritic cell aggresome-like induced structures) originally described in lipopolysaccharide-stimulated dendritic cells as storage compartments for polyubiquitinated proteins prior to their degradation (18). ALIS or DALIS are inclusion bodies where newly synthesized ubiquitinated proteins transiently accumulate, many of which are defective ribosomal products (17)(18)(19). However, also long lived proteins are targeted to ALIS (17).…”

mentioning

confidence: 99%

p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy

Pankiv

Clausen

Lamark

et al. 2007

Journal of Biological Chemistry

3,997

3,159

View full text Add to dashboard Cite

Protein degradation by basal constitutive autophagy is important to avoid accumulation of polyubiquitinated protein aggregates and development of neurodegenerative diseases. The polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy. It is found in cellular inclusion bodies together with polyubiquitinated proteins and in cytosolic protein aggregates that accumulate in various chronic, toxic, and degenerative diseases. Here we show for the first time a direct interaction between p62 and the autophagic effector proteins LC3A and -B and the related ␥-aminobutyrate receptor-associated protein and ␥-aminobutyrate receptor-associated-like proteins. The binding is mediated by a 22-residue sequence of p62 containing an evolutionarily conserved motif. To monitor the autophagic sequestration of p62-and LC3-positive bodies, we developed a novel pH-sensitive fluorescent tag consisting of a tandem fusion of the red, acid-insensitive mCherry and the acid-sensitive green fluorescent proteins. This approach revealed that p62-and LC3-positive bodies are degraded in autolysosomes. Strikingly, even rather large p62-positive inclusion bodies (2 m diameter) become degraded by autophagy. The specific interaction between p62 and LC3, requiring the motif we have mapped, is instrumental in mediating autophagic degradation of the p62-positive bodies. We also demonstrate that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation. In fact, p62 bodies and these structures are indistinguishable. Taken together, our results clearly suggest that p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.

show abstract

Dendritic cell aggresome-like induced structures are dedicated areas for ubiquitination and storage of newly synthesized defective proteins

Cited by 138 publications

References 30 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

Antigen‐presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis

p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy

Contact Info

Product

Resources

About