scholarly journals Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis

2020 ◽  
Vol 117 (45) ◽  
pp. 27980-27988 ◽  
Author(s):  
Estefanía Lucendo ◽  
Mónica Sancho ◽  
Fabio Lolicato ◽  
Matti Javanainen ◽  
Waldemar Kulig ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Somatic Mutations ◽  
Transmembrane Domain ◽  
Active Role ◽  
Protein Family ◽  
Mitochondrial Outer Membrane ◽  
Dependent Manner ◽  
Mitochondrial Targeting ◽  
Carboxyl Terminal

The Bcl-2 protein family comprises both pro- and antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein family members can modulate apoptosis; however, the transmembrane interactome of the antiapoptotic protein Mcl-1 remains largely unexplored. Here, we demonstrate that the Mcl-1 TMD forms homooligomers in the mitochondrial membrane, competes with full-length Mcl-1 protein with regards to its antiapoptotic function, and induces cell death in a Bok-dependent manner. While the Bok TMD oligomers locate preferentially to the endoplasmic reticulum (ER), heterooligomerization between the TMDs of Mcl-1 and Bok predominantly takes place at the mitochondrial membrane. Strikingly, the coexpression of Mcl-1 and Bok TMDs produces an increase in ER mitochondrial-associated membranes, suggesting an active role of Mcl-1 in the induced mitochondrial targeting of Bok. Finally, the introduction of Mcl-1 TMD somatic mutations detected in cancer patients alters the TMD interaction pattern to provide the Mcl-1 protein with enhanced antiapoptotic activity, thereby highlighting the clinical relevance of Mcl-1 TMD interactions.

scholarly journals Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States?

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 289
Author(s):  
Emelie E. Aspholm ◽  
Irena Matečko-Burmann ◽  
Björn M. Burmann
Keyword(s):  
Molecular Chaperones ◽  
Mitochondrial Membrane ◽  
Structural Transition ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Protein Aggregates ◽  
Active Role ◽  
Proteolytic Processing ◽  
Membrane Disruption

The property of molecular chaperones to dissolve protein aggregates of Parkinson-related α-synuclein has been known for some time. Recent findings point to an even more active role of molecular chaperones preventing the transformation of α-synuclein into pathological states subsequently leading to the formation of Lewy bodies, intracellular inclusions containing protein aggregates as well as broken organelles found in the brains of Parkinson’s patients. In parallel, a short motif around Tyr39 was identified as being crucial for the aggregation of α-synuclein. Interestingly, this region is also one of the main segments in contact with a diverse pool of molecular chaperones. Further, it could be shown that the inhibition of the chaperone:α-synuclein interaction leads to a binding of α-synuclein to mitochondria, which could also be shown to lead to mitochondrial membrane disruption as well as the possible proteolytic processing of α-synuclein by mitochondrial proteases. Here, we will review the current knowledge on the role of molecular chaperones in the regulation of physiological functions as well as the direct consequences of impairing these interactions—i.e., leading to enhanced mitochondrial interaction and consequential mitochondrial breakage, which might mark the initial stages of the structural transition of α-synuclein towards its pathological states.

scholarly journals Quorum-sensing regulation in rhizobia and its role in symbiotic interactions with legumes

2007 ◽  
Vol 362 (1483) ◽  
pp. 1149-1163 ◽  
Author(s):  
Maria Sanchez-Contreras ◽  
Wolfgang D Bauer ◽  
Mengsheng Gao ◽  
Jayne B Robinson ◽  
J Allan Downie
Keyword(s):  
Quorum Sensing ◽  
Potential Role ◽  
Active Role ◽  
Dependent Manner ◽  
Homoserine Lactones ◽  
Signalling Molecules ◽  
Sensing Systems ◽  
Symbiotic Interactions ◽  
Regulatory Systems

Legume-nodulating bacteria (rhizobia) usually produce N -acyl homoserine lactones, which regulate the induction of gene expression in a quorum-sensing (or population-density)-dependent manner. There is significant diversity in the types of quorum-sensing regulatory systems that are present in different rhizobia and no two independent isolates worked on in detail have the same complement of quorum-sensing genes. The genes regulated by quorum sensing appear to be rather diverse and many are associated with adaptive aspects of physiology that are probably important in the rhizosphere. It is evident that some aspects of rhizobial physiology related to the interaction between rhizobia and legumes are influenced by quorum sensing. However, it also appears that the legumes play an active role, both in terms of interfering with the rhizobial quorum-sensing systems and responding to the signalling molecules made by the bacteria. In this article, we review the diversity of quorum-sensing regulation in rhizobia and the potential role of legumes in influencing and responding to this signalling system.

scholarly journals Tom20 Mediates Localization of mRNAs to Mitochondria in a Translation-Dependent Manner

2009 ◽  
Vol 30 (1) ◽  
pp. 284-294 ◽  
Author(s):  
Erez Eliyahu ◽  
Lilach Pnueli ◽  
Daniel Melamed ◽  
Tanja Scherrer ◽  
André P. Gerber ◽  
...  
Keyword(s):  
Large Scale ◽  
Dna Microarrays ◽  
Protein Transport ◽  
Yeast Cells ◽  
Mitochondrial Proteins ◽  
Mitochondrial Outer Membrane ◽  
Dependent Manner ◽  
Mitochondrial Targeting ◽  
Double Knockout ◽  
Mitochondrial Fractions

ABSTRACT mRNAs encoding mitochondrial proteins are enriched in the vicinity of mitochondria, presumably to facilitate protein transport. A possible mechanism for enrichment may involve interaction of the translocase of the mitochondrial outer membrane (TOM) complex with the precursor protein while it is translated, thereby leading to association of polysomal mRNAs with mitochondria. To test this hypothesis, we isolated mitochondrial fractions from yeast cells lacking the major import receptor, Tom20, and compared their mRNA repertoire to that of wild-type cells by DNA microarrays. Most mRNAs encoding mitochondrial proteins were less associated with mitochondria, yet the extent of decrease varied among genes. Analysis of several mRNAs revealed that optimal association of Tom20 target mRNAs requires both translating ribosomes and features within the encoded mitochondrial targeting signal. Recently, Puf3p was implicated in the association of mRNAs with mitochondria through interaction with untranslated regions. We therefore constructed a tom20Δ puf3Δ double-knockout strain, which demonstrated growth defects under conditions where fully functional mitochondria are required. Mislocalization effects for few tested mRNAs appeared stronger in the double knockout than in the tom20Δ strain. Taken together, our data reveal a large-scale mRNA association mode that involves interaction of Tom20p with the translated mitochondrial targeting sequence and may be assisted by Puf3p.

scholarly journals Parkin-mediated ubiquitination contributes to the constitutive turnover of mitochondrial fission factor (Mff)

2019 ◽  
Author(s):  
Laura Lee ◽  
Richard Seager ◽  
Kevin A. Wilkinson ◽  
Jeremy M. Henley
Keyword(s):  
Membrane Protein ◽  
Ubiquitin Ligase ◽  
Mitochondrial Membrane ◽  
Mitochondrial Fission ◽  
Protein Composition ◽  
Mitochondrial Outer Membrane ◽  
Dependent Manner ◽  
Mitochondrial Network ◽  
Functionally Impaired ◽  
Mitochondrial Membrane Protein

AbstractThe mitochondrial outer membrane protein Mitochondrial Fission Factor (Mff) plays a key role in both physiological and pathological fission. It is well established that in stressed or functionally impaired mitochondria the PINK1 recruits the ubiquitin ligase Parkin which ubiquitinates Mff to facilitate the removal of defective mitochondria and maintain the integrity mitochondrial network. Here we show that, in addition to this clearance pathway, Parkin also ubiquitinates Mff in a PINK1-dependent manner under basal, non-stressed conditions to regulate constitutive Mff turnover. We further show that removing Parkin with shRNA knockdown does not completely prevent Mff ubiquitination under these conditions indicating that at least one other ubiquitin ligase contributes to Mff proteostasis. These data demonstrate that Parkin plays a role in physiological maintenance of mitochondrial membrane protein composition in healthy mitochondria through constitutive low-level activation.

scholarly journals How does the TOM complex mediate insertion of precursor proteins into the mitochondrial outer membrane?

2005 ◽  
Vol 171 (3) ◽  
pp. 419-423 ◽  
Author(s):  
Doron Rapaport
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Mitochondrial Outer Membrane ◽  
Outer Face ◽  
Outer Mitochondrial Membrane ◽  
Lipid Core ◽  
Tom Complex ◽  
Precursor Proteins

A multisubunit translocase of the outer mitochondrial membrane (TOM complex) mediates both the import of mitochondrial precursor proteins into the internal compartments of the organelle and the insertion of proteins residing in the mitochondrial outer membrane. The proposed β-barrel structure of Tom40, the pore-forming component of the translocase, raises the question of how the apparent uninterrupted β-barrel topology can be compatible with a role of Tom40 in releasing membrane proteins into the lipid core of the bilayer. In this review, I discuss insertion mechanisms of proteins into the outer membrane and present alternative models based on the opening of a multisubunit β-barrel TOM structure or on the interaction of outer membrane precursors with the outer face of the Tom40 β-barrel structure.

scholarly journals Involvement of Noxa in Cellular Apoptotic Responses to Interferon, Double-stranded RNA, and Virus Infection

2005 ◽  
Vol 280 (16) ◽  
pp. 15561-15568 ◽  
Author(s):  
Yaping Sun ◽  
Douglas W. Leaman
Keyword(s):  
Mitochondrial Protein ◽  
Membrane Integrity ◽  
Ectopic Expression ◽  
Human Tumor ◽  
Mitochondrial Outer Membrane ◽  
Dependent Manner ◽  
Mitochondrial Targeting ◽  
Double Stranded Rna ◽  
Bh3 Domain ◽  
Apoptosis Protein

Double-stranded RNA (dsRNA) accumulates in virally infected cells, leading to induction of genes encoding proteins involved in signaling, apoptosis, protein synthesis/processing, and cell metabolism. Noxa is a BH3-containing mitochondrial protein that contributes to apoptosis by disrupting mitochondrial outer membrane integrity. Here we demonstrate potent induction of Noxa expression by exposure of cells to dsRNA, interferon (IFN), and virus. Noxa induction was confirmed by using reverse transcriptase-PCR and immunoblot analyses in multiple human tumor cell lines. Importantly, Noxa regulation by IFN and dsRNA was independent of p53, thereby identifying a novel mechanism of Noxa induction. Ectopic expression of Noxa in HT1080 fibrosarcoma cells enhanced cellular sensitivity to viral or dsRNA/actinomycin D-induced apoptosis, typified by enhanced cytochromecrelease from the mitochondrial to the cytosolic fraction and increased cleavage of caspases 3 and 9. Point and deletion mutations of Noxa confirmed that both the BH3 domain and the mitochondrial-targeting domain were necessary for enhanced cellular apoptotic responses to dsRNA, IFN, or virus. Treatment of cells with dsRNA or virus, but not etoposide, induced interaction between Noxa and Bax that required an intact Noxa BH3 domain. Interestingly, the Noxa mitochondrial-targeting domain deletion mutant interacted with Bax in a dsRNA-dependent manner and redirected Bax away from the mitochondria, thus acting as a dominant-negative protein. Together, these data suggest that Noxa is an important component of the innate immune response of cells to viral infection, leading to enhanced cellular apoptosis that may play a role in limiting viral dissemination.

scholarly journals Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation

2021 ◽  
Author(s):  
Scott P. Lyons ◽  
Elora C. Greiner ◽  
Lauren E. Cressey ◽  
Mark E. Adamo ◽  
Arminja N. Kettenbach
Keyword(s):  
Cell Lines ◽  
Regulatory Subunit ◽  
Regulatory Function ◽  
Dependent Manner ◽  
Catalytic Subunits ◽  
Transformed Cell ◽  
The Family ◽  
Carboxyl Terminal ◽  
Transformed Cell Lines

The family of Phosphoprotein Phosphatases (PPPs) is responsible for most cellular serine and threonine dephosphorylation. PPPs achieve substrate specificity and selectivity by forming multimeric holoenzymes. PPP holoenzyme assembly is tightly controlled, and changes in the cellular repertoire of PPPs are linked to human disease, including cancer and neurodegeneration. For PP2A, PP4, and PP6, holoenzyme formation is in part regulated by carboxyl (C)-terminal methyl-esterification (often referred to as methylation). Here, we use mass spectrometry-based proteomics, methylation-ablating mutations, and genome editing to elucidate the role of C-terminal methylation on PP2A, PP4, and PP6 holoenzyme assembly. We find that the catalytic subunits of PP2A, PP4, and PP6 are frequently methylated in cancer cells and that deletion of the C-terminal leucine faithfully recapitulates loss of methylation. We observe that loss of PP2A methylation consistently reduced B55, B56, and B72 regulatory subunit binding in cancer and non-transformed cell lines. However, Striatin subunit binding is only affected in non-transformed cells. For PP4, we find that PP4R1 and PP4R3β bind in a methylation-dependent manner. Intriguingly, loss of methylation does not affect PP6 holoenzymes. Our analyses demonstrate in an unbiased, comprehensive, and isoform-specific manner the crucial regulatory function of endogenous PPP methylation in transformed and non-transformed cell lines.

scholarly journals Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon by Binding to MAVS and Decreasing Mitochondrial Membrane Potential

2012 ◽  
Vol 86 (16) ◽  
pp. 8359-8366 ◽  
Author(s):  
Zsuzsanna T. Varga ◽  
Alesha Grant ◽  
Balaji Manicassamy ◽  
Peter Palese
Keyword(s):  
Influenza Virus ◽  
Membrane Potential ◽  
Molecular Mechanism ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Transmembrane Domain ◽  
Type I Interferon ◽  
Adaptor Protein ◽  
Type I ◽  
Dependent Manner

PB1-F2 is a small, 87- to 90-amino-acid-long protein encoded by the +1 alternate open reading frame of the PB1 gene of most influenza A virus strains. It has been shown to contribute to viral pathogenicity in a host- and strain-dependent manner, and we have previously discovered that a serine at position 66 (66S) in the PB1-F2 protein increases virulence of the 1918 and H5N1 pandemic viruses. Recently, we have shown that PB1-F2 inhibits the induction of type I interferon (IFN) at the level of the MAVS adaptor protein. However, the molecular mechanism for the IFN antagonist function of PB1-F2 has remained unclear. In the present study, we demonstrated that the C-terminal portion of the PB1-F2 protein binds to MAVS in a region that contains the transmembrane domain. Strikingly, PB1-F2 66S was observed to bind to MAVS more efficiently than PB1-F2 66N. We also tested the effect of PB1-F2 on the IFN antagonist functions of the polymerase proteins PB1, PB2, and PA and observed enhanced IFN inhibition by the PB1 and PB2 proteins in combination with PB1-F2 but not by the PA protein. Using a flow cytometry-based assay, we demonstrate that the PB1-F2 protein inhibits MAVS-mediated IFN synthesis by decreasing the mitochondrial membrane potential (MMP). Interestingly, PB1-F2 66S affected the MMP more efficiently than wild-type PB1-F2. In summary, the results of our study identify the molecular mechanism by which the influenza virus PB1-F2 N66S protein increases virulence.

scholarly journals Myrica rubraExtracts Protect the Liver from CCl4-Induced Damage

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Lizhi Xu ◽  
Jing Gao ◽  
Yucai Wang ◽  
Wen Yu ◽  
Xiaoning Zhao ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Liver Mitochondria ◽  
Mitochondrial Outer Membrane ◽  
Free Calcium ◽  
Dependent Manner ◽  
Protective Effects ◽  
Nuclear Condensation ◽  
Serum Aspartate Aminotransferase

The relationship between the expression of mitochondrial voltage-dependent anion channels (VDACs) and the protective effects ofMyrica rubraSieb. Et Zucc fruit extract (MCE) against carbon tetrachloride (CCl4)-induced liver damage was investigated. Pretreatment with 50 mg kg−1, 150 mg kg−1or 450 mg kg−1MCE significantly blocked the CCl4-induced increase in both serum aspartate aminotransferase (sAST) and serum alanine aminotransferase (sALT) levels in mice (P< .05 or .01 versus CCl4group). Ultrastructural observations of decreased nuclear condensation, ameliorated mitochondrial fragmentation of the cristae and less lipid deposition by an electron microscope confirmed the hepatoprotection. The mitochondrial membrane potential dropped from −191.94 ± 8.84 mV to −132.06 ± 12.26 mV (P< .01) after the mice had been treated with CCl4. MCE attenuated CCl4-induced mitochondrial membrane potential dissipation in a dose-dependent manner. At a dose of 150 or 450 mg kg−1of MCE, the mitochondrial membrane potentials were restored (P< .05). Pretreatment with MCE also prevented the elevation of intra-mitochondrial free calcium as observed in the liver of the CCl4-insulted mice (P< .01 versus CCl4group). In addition, MCE treatment (50–450 mg kg−1) significantly increased both transcription and translation of VDAC inhibited by CCl4. The above data suggest that MCE mitigates the damage to liver mitochondria induced by CCl4, possibly through the regulation of mitochondrial VDAC, one of the most important proteins in the mitochondrial outer membrane.

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