The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides

Goldberg, Alfred L.; Cascio, Paolo; Šarić, Tomo; Rock, Kenneth L.

doi:10.1016/s0161-5890(02)00098-6

Cited by 303 publications

(219 citation statements)

References 101 publications

Supporting

Mentioning

211

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, they also found that transgenic mice expressing a mutant form of H2-K b lacking tyrosine in this position mounted reduced CTL responses to two immunodominant viral epitopes, and DC from these mice did not process and present OVA in vitro. They did not investigate where processing occurred but, to accommodate data in similar systems showing inhibition by drugs that block proteasomes, discussed the possibility of it taking place in phagosomes [29,30].…”

Section: Discussionmentioning

confidence: 99%

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Chen

Jondal

2004

Eur J Immunol

View full text Add to dashboard Cite

Exogenous proteins can be processed by antigen-presenting cells for the generation of MHC class I-restricted T cell responses. Where this occurs is not clear, although both transfer of internalized antigen into the cytosol and alternative processing in endolysosomes and phagosomes have been reported. Here we have studied the capacity of bone marrowderived mouse myeloid dendritic cells (DC) to process the OVA protein for peptide presentation by H2-K b . We have found that immature DC (iDC), both wild-type and transporter associated with antigen processing (TAP)-deficient cells, can transiently process OVA in a pathway which is resistant to inhibitors of the classical MHC class I pathway including the Golgi inhibitor Brefeldin A (BFA) and the proteasome inhibitor lactacystin. This alternative pathway is not found in subcultured DC with an intermediate maturity (imDC) or in resting, IL-3 expanded macrophages but can be re-expressed in imDC if these are activated by an immunostimulatory CpG oligonucleotide. Both iDC and CpG-activated DC were found to process OVA by regurgitation. In addition, we found that iDC secrete proteolytic enzymes into the supernatant, which can process OVA in the extracellular phase. These results suggest that multiple pathways exist for the processing of exogenous protein antigens into MHC class Ibinding peptides.

show abstract

Section: Discussionmentioning

confidence: 99%

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Chen

Jondal

2004

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…However, a mixture of the standard and i-proteasome catalytic subunits may be found at the 20S catalytic core (Dahlmann et al, 2000), and was shown to contribute to differences in catalytic core enzymatic characteristics and cleavage of model substrates (Dahlmann et al, 2000). The iproteasomes play an important role in the immune system, generating immunogenic peptides for antigen presentation on MHC class I and recognition by cytotoxic T lymphocytes (Rock et al, 1994;Goldberg et al, 2002). Although in young healthy human brain i-proteasomes are almost absent, they have been detected in brain areas from elderly subjects as well as from patients affected by Alzheimer (Mishto et al, 2006) and Huntington diseases (Diaz-Hernandez et al, 2003), and in Multiple Sclerosis (Mishto et al, 2010).…”

Section: Immunoproteasomementioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

117

View full text Add to dashboard Cite

A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

show abstract

“…p97/VCP, upon its binding to HDAC6, is able to extract HDAC6 bound to ubiquitinated proteins and therefore allows their further processing. A finely tuned equilibrium of cellular concentrations of HDAC6 and p97/VCP could therefore be critical in the determination of the fate of ubiquitinated cellular proteins, mostly consisting of misfolded proteins (Goldberg et al, 2002). An excess of HDAC6 would favor their accumulation in cells, while an increase of the p97/VCP concentration would accelerate the processing of these proteins (Boyault et al, 2006; Figure 2).…”

Section: Ubiquitin-dependent Functions Of Hdac6mentioning

confidence: 99%

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

et al. 2007

View full text Add to dashboard Cite

Histone deacetylase 6 (HDAC6) is a unique enzyme with specific structural and functional features. It is actively or stably maintained in the cytoplasm and is the only member, within the histone deacetylase family, that harbors a full duplication of its deacetylase homology region followed by a specific ubiquitin-binding domain at the C-terminus end. Accordingly, this deacetylase functions at the heart of a cellular regulatory mechanism capable of coordinating various cellular functions largely relying on the microtubule network. Moreover, HDAC6 action as a regulator of the HSP90 chaperone activity adds to the multifunctionality of the protein, and allows us to propose a critical role for HDAC6 in mediating and coordinating various cellular events in response to different stressful stimuli.

show abstract

The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides

Cited by 303 publications

References 101 publications

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

Contact Info

Product

Resources

About