Proteomic Analysis of Mitochondrial Protein Turnover: Identification of Novel Substrate Proteins of the Matrix Protease Pim1

Major, Tamara; Janowsky, Birgit von; Ruppert, Thomas; Mogk, Axel; Voos, Wolfgang

doi:10.1128/mcb.26.3.762-776.2006

Cited by 97 publications

(95 citation statements)

References 53 publications

(76 reference statements)

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“…In this classical pathway, the antigenic peptide derives from cytosolic CLPP polypeptides before addressing to mitochondria. Another possibility is that CLPP is degraded by intramitochondrial proteolytic systems such as Pim1, other proteases of the AAA family (42,43), or the CLPP system itself. The resulting peptides are actively transported across the inner mitochondrial membrane into the intermembrane space, then cross the outer membrane by passive diffusion through porins or through the general import pore of the outer membrane (44).…”

Section: Discussionmentioning

confidence: 99%

Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases

Corbière

Chapiro²,

Stroobant³

et al. 2011

Cancer Research

157

117

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A core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor b (TCRb) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCRb sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumorspecific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCRb sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-g treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly tumor-specific antigens contributes decisively to tumor regression. Cancer Res; 71(4); 1253-62. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases

Corbière

Chapiro²,

Stroobant³

et al. 2011

Cancer Research

157

117

View full text Add to dashboard Cite

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“…It has been suggested that during the absence of substrates or cosubstrates a catalytic center or a metal binding site of a protein may be damaged; similarly, a protein can undergo structural perturbation without other components that normally hold it in native conformation (7,17,18,(31)(32)(33)41). These proteins could display a nonfunctional, unprotected, or even "unemployed" state, and it can be hypothesized that ATP-dependent proteases recognize these idle and defective proteins and degrade them.…”

Section: Discussionmentioning

confidence: 99%

Clp-Dependent Proteolysis Down-Regulates Central Metabolic Pathways in Glucose-StarvedBacillus subtilis

et al. 2008

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Entry into stationary phase in Bacillus subtilis is linked not only to a redirection of the gene expression program but also to posttranslational events such as protein degradation. Using 35 S-labeled methionine pulse-chase labeling and two-dimensional polyacrylamide gel electrophoresis we monitored the intracellular proteolysis pattern during glucose starvation. Approximately 200 protein spots diminished in the wild-type cells during an 8-h time course. The degradation rate of at least 80 proteins was significantly reduced in clpP, clpC, and clpX mutant strains. Enzymes of amino acid and nucleotide metabolism were overrepresented among these Clp substrate candidates. Notably, several first-committed-step enzymes for biosynthesis of aromatic and branched-chain amino acids, cell wall precursors, purines, and pyrimidines appeared as putative Clp substrates. Radioimmunoprecipitation demonstrated GlmS, IlvB, PurF, and PyrB to be novel ClpCP targets. Our data imply that Clp proteases down-regulate central metabolic pathways upon entry into a nongrowing state and thus contribute to the adaptation to nutrient starvation. Proteins that are obviously nonfunctional, unprotected, or even "unemployed" seem to be recognized and proteolyzed by Clp proteases when the resources for growth become limited.

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“…SOD2, peroxiredoxin3, mitochondrial thioredoxin, and mitochondrial thioredoxin reductase have been found to be the main components of the antioxidant system (20)(21)(22). Mitochondria are considered a principle source and target of reactive oxygen species (ROS) (23), and the collapse of the mitochondrial transmembrane potential can initiate the signaling cascades involved in apoptosis (24)(25)(26). It is well known that the cause of ADR cardiotoxicity is multifactorial, even though most ADR-induced cardiac effects can be attributed to ROS formation, which ultimately results in myocyte apoptosis (2).…”

Section: Cardiotoxicitymentioning

confidence: 99%

Comparative Mitochondrial Proteomic Analysis of Raji Cells Exposed to Adriamycin

Jiang

Sun

Fang

et al. 2009

Mol Med

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The antitumor mechanisms of adriamycin (ADR) have been thought to contribute to induction of apoptosis and inefficiency of DNA repair, processes that are to a large extent mediated by mitochondria. This study aimed to investigate characteristics of ADR, including its antineoplastic activity, drug resistance, and unexpected toxicity in non-Hodgkin lymphoma (NHL) Raji cells at the mitochondrial proteomic level. The alterations of the mitochondrial proteome of Raji cells treated with ADR were analyzed by twodimensional differential in-gel electrophoresis (2D-DIGE) coupled with linear ion trap quadrupole-electrospray ionization tandem mass spectrometry (LTQ-ESI-MS/MS). The altered patterns of three identified proteins were validated by Western blot and analyzed by pathway studio software. The results showed that 34 proteins were downregulated and 3 proteins upregulated in the study group compared with the control group. The differentially expressed proteins distributed their functions in reduction-oxidation reactions, DNA repair, cell cycle regulation, transporters and channels, and oxidative phosphorylation. Furthermore, heat shock protein 70 (HSP70), ATP-binding cassette transporter isoform B6 (ABCB6), and prohibitin (PHB) identified in this study may be closely related to chemoresistance and could serve as potential chemotherapeutic targets for NHL. Collectively, these results suggest that specific mitochondrial proteins are uniquely susceptible to alterations in abundance following exposure to ADR and carry implications for the investigation of therapeutic and prognostic markers. Further studies focusing on these identified proteins will be used to predict treatment response and reverse apoptosis resistance, and to explore drug-combination strategies associated with ADR for NHL therapy.

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Proteomic Analysis of Mitochondrial Protein Turnover: Identification of Novel Substrate Proteins of the Matrix Protease Pim1

Cited by 97 publications

References 53 publications

Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases

Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases

Clp-Dependent Proteolysis Down-Regulates Central Metabolic Pathways in Glucose-StarvedBacillus subtilis

Comparative Mitochondrial Proteomic Analysis of Raji Cells Exposed to Adriamycin

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