Presenting mitochondrial antigens: PINK1, Parkin and MDVs steal the show

Roberts, Rosalind F.; Fon, Edward A.

doi:10.1038/cr.2016.104

Cited by 25 publications

(21 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These notably comprise PRKN, PINK1, and SQSTM1 (98–101). In the recent years, major works provided evidence that, in neurons and immune cells, functional defects in such genes hamper mitophagy (a specialized form of autophagy), stimulate the inflammasome pathway and foster the presentation of mitochondrial antigens by MHC class I molecules (33, 102, 103). However, these findings do not render account for the existence of HLA class II-restricted T-cell responses against neurodegeneration-associated proteins.…”

Section: Discussionmentioning

confidence: 99%

Common Neurodegeneration-Associated Proteins Are Physiologically Expressed by Human B Lymphocytes and Are Interconnected via the Inflammation/Autophagy-Related Proteins TRAF6 and SQSTM1

2019

View full text Add to dashboard Cite

There is circumstantial evidence that, under neurodegenerative conditions, peptides deriving from aggregated or misfolded specific proteins elicit adaptive immune responses. On another hand, several genes involved in familial forms of neurodegenerative diseases exert key innate immune functions. However, whether or not such observations are causally linked remains unknown. To start addressing this issue, we followed a systems biology strategy based on the mining of large proteomics and immunopeptidomics databases. First, we retrieved the expression patterns of common neurodegeneration-associated proteins in two professional antigen-presenting cells, namely B lymphocytes and dendritic cells. Surprisingly, we found that under physiological conditions, numerous neurodegeneration-associated proteins are abundantly expressed by human B lymphocytes. A survey of the human proteome allowed us to map a unique protein-protein interaction network linking common neurodegeneration-associated proteins and their first shell interactors in human B lymphocytes. Interestingly, network connectivity analysis identified two major hubs that both relate with inflammation and autophagy, namely TRAF6 (TNF Receptor Associated Factor 6) and SQSTM1 (Sequestosome-1). Moreover, the mapped network in B lymphocytes comprised two additional hub proteins involved in both inflammation and autoimmunity: HSPA8 (Heat Shock Protein Family A Member 8 also known as HSC70) and HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1). Based on these results, we then explored the Immune Epitope Database “IEDB-AR” and actually found that a large share of neurodegeneration-associated proteins were previously reported to provide endogenous MHC class II-binding peptides in human B lymphocytes. Of note, peptides deriving from amyloid beta A4 protein, sequestosome-1 or profilin-1 were reported to bind multiple allele-specific MHC class II molecules. In contrast, peptides deriving from microtubule-associated protein tau, presenilin 2 and serine/threonine-protein kinase TBK1 were exclusively reported to bind MHC molecules encoded by the HLA-DRB1 1501 allele, a recently-identified susceptibility gene for late onset Alzheimer's disease. Finally, we observed that the whole list of proteins reported to provide endogenous MHC class II-binding peptides in human B lymphocytes is specifically enriched in neurodegeneration-associated proteins. Overall, our work indicates that immunization against neurodegeneration-associated proteins might be a physiological process which is shaped, at least in part, by B lymphocytes.

show abstract

Section: Discussionmentioning

confidence: 99%

Common Neurodegeneration-Associated Proteins Are Physiologically Expressed by Human B Lymphocytes and Are Interconnected via the Inflammation/Autophagy-Related Proteins TRAF6 and SQSTM1

2019

View full text Add to dashboard Cite

show abstract

“…In response to cellular stress, a novel PINK1-Parkin-mediated MDV pathway exports mitochondrial-derived self-antigens for presentation at the cell surface, triggering an immune response [50]. This unexpected discovery of MitAP provides an interesting link between autoimmunity and PD [51]. The complexity of signalling pathways regulating the delivery of damaged mitochondria to the lysosome also needs to be evaluated in light of emerging findings in organelle crosstalk [52].…”

Section: Emerging Themes From Cell Biology To Pathologymentioning

confidence: 94%

PINK1 and Parkin: emerging themes in mitochondrial homeostasis

McWilliams

Muqit

2017

Current Opinion in Cell Biology

275

235

View full text Add to dashboard Cite

The Parkinson's disease (PD)-associated protein kinase, PTEN-induced putative kinase1 (PINK1), and ubiquitin E3 ligase Parkin, function in a common signalling pathway known to regulate mitochondrial network homeostasis and quality control, including mitophagy. The multistep activation of this pathway, as well as an unexpected convergence between the post-translational modifications of ubiquitylation and phosphorylation, has added breadth to our understanding of cellular damage responses during human disease. In concert with these new insights in signal transduction, unique modalities and signatures of vertebrate mitophagy have been unravelled in vivo for the very first time. The cell biology of mammalian mitophagy, and the roles of PINK1-Parkin signalling in vivo have emerged to be more complex than previously thought.

show abstract

“…In addition to its roles in mitophagy and mitochondrial dynamics, Parkin targets the transcriptional repressor of PGC-1α PARIS (ZNF746, zinc finger protein 746), favoring mitochondrial biogenesis [153]. Finally, a role of Parkin in the production of mitochondrial-derived vesicles playing a role in mitochondrial quality control has also been revealed [154,155,156,157,158].…”

Section: The Emerging Roles Of Parkin and Foxo3-dependant Mul1 Patmentioning

confidence: 99%

Recent Data on Cellular Component Turnover: Focus on Adaptations to Physical Exercise

Sanchez

Candau

Bernardi³

2019

Cells

View full text Add to dashboard Cite

Significant progress has expanded our knowledge of the signaling pathways coordinating muscle protein turnover during various conditions including exercise. In this manuscript, the multiple mechanisms that govern the turnover of cellular components are reviewed, and their overall roles in adaptations to exercise training are discussed. Recent studies have highlighted the central role of the energy sensor (AMP)-activated protein kinase (AMPK), forkhead box class O subfamily protein (FOXO) transcription factors and the kinase mechanistic (or mammalian) target of rapamycin complex (MTOR) in the regulation of autophagy for organelle maintenance during exercise. A new cellular trafficking involving the lysosome was also revealed for full activation of MTOR and protein synthesis during recovery. Other emerging candidates have been found to be relevant in organelle turnover, especially Parkin and the mitochondrial E3 ubiquitin protein ligase (Mul1) pathways for mitochondrial turnover, and the glycerolipids diacylglycerol (DAG) for protein translation and FOXO regulation. Recent experiments with autophagy and mitophagy flux assessment have also provided important insights concerning mitochondrial turnover during ageing and chronic exercise. However, data in humans are often controversial and further investigations are needed to clarify the involvement of autophagy in exercise performed with additional stresses, such as hypoxia, and to understand the influence of exercise modality. Improving our knowledge of these pathways should help develop therapeutic ways to counteract muscle disorders in pathological conditions.

show abstract

Presenting mitochondrial antigens: PINK1, Parkin and MDVs steal the show

Cited by 25 publications

References 10 publications

Common Neurodegeneration-Associated Proteins Are Physiologically Expressed by Human B Lymphocytes and Are Interconnected via the Inflammation/Autophagy-Related Proteins TRAF6 and SQSTM1

Common Neurodegeneration-Associated Proteins Are Physiologically Expressed by Human B Lymphocytes and Are Interconnected via the Inflammation/Autophagy-Related Proteins TRAF6 and SQSTM1

PINK1 and Parkin: emerging themes in mitochondrial homeostasis

Recent Data on Cellular Component Turnover: Focus on Adaptations to Physical Exercise

Contact Info

Product

Resources

About