Posttranslational control of the scaffold for Fe–S cluster biogenesis as a compensatory regulatory mechanism

Ciesielski, Szymon J.; Craig, Elizabeth A.

doi:10.1007/s00294-016-0618-y

Cited by 6 publications

(7 citation statements)

References 36 publications

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“…First, we hypothesized that VDAC might be an Fe-S protein and that the assembly of its Fe-S cluster could protect it from truncation. Fe-S clusters are often necessary to maintain protein structure [ 54 ]. Contrarily, in glutamine phosphoribosylpyrophosphate aminotransferase (GPAT), the insertion of its cluster is necessary for the cleavage of the N-terminal residues to generate its mature form [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation

et al. 2018

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Biogenesis of iron-sulfur clusters (ISC) is essential to almost all forms of life and involves complex protein machineries. This process is initiated within the mitochondrial matrix by the ISC assembly machinery. Cohort and case report studies have linked mutations in ISC assembly machinery to severe mitochondrial diseases. The voltage-dependent anion channel (VDAC) located within the mitochondrial outer membrane regulates both cell metabolism and apoptosis. Recently, the C-terminal truncation of the VDAC1 isoform, termed VDAC1-ΔC, has been observed in chemoresistant late-stage tumor cells grown under hypoxic conditions with activation of the hypoxia-response nuclear factor HIF-1α. These cells harbored atypical enlarged mitochondria. Here, we show for the first time that depletion of several proteins of the mitochondrial ISC machinery in normoxia leads to a similar enlarged mitochondria phenotype associated with accumulation of VDAC1-ΔC. This truncated form of VDAC1 accumulates in the absence of HIF-1α and HIF-2α activations and confers cell resistance to drug-induced apoptosis. Furthermore, we show that when hypoxia and siRNA knock-down of the ISC machinery core components are coupled, the cell phenotype is further accentuated, with greater accumulation of VDAC1-ΔC. Interestingly, we show that hypoxia promotes the downregulation of several proteins (ISCU, NFS1, FXN) involved in the early steps of mitochondrial Fe-S cluster biogenesis. Finally, we have identified the mitochondria-associated membrane (MAM) localized Fe-S protein CISD2 as a link between ISC machinery downregulation and accumulation of anti-apoptotic VDAC1-ΔC. Our results are the first to associate dysfunction in Fe-S cluster biogenesis with cleavage of VDAC1, a form which has previously been shown to promote tumor resistance to chemotherapy, and raise new perspectives for targets in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation

et al. 2018

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“…, 2010 ; Stemmler et al. , 2010 ; Ciesielski and Craig, 2017 ). Destabilized ISD complex leads to decreased activity of ISC-containing proteins ( Adam et al.…”

Section: Discussionmentioning

confidence: 99%

“…, 2010 ; Stemmler et al. , 2010 ; Ciesielski and Craig, 2017 ). The [2Fe2S] cluster is formed on the scaffold protein Isu1/Isu2 ( Schilke et al.…”

Section: Introductionmentioning

confidence: 99%

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Respiratory chain supercomplexes associate with the cysteine desulfurase complex of the iron–sulfur cluster assembly machinery

Böttinger

Mårtensson

Song

et al. 2018

MBoC

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“…This short loop has been reported to also be involved in binding of frataxin, a key component of the FeS synthesis complex assembled around cysteine desulfurase ( Prischi et al, 2010 ; Manicki et al, 2014 ; Fox et al, 2019 ). Moreover, Isu/IscU is a substrate for the ATP dependent protease LON (known as Pim1 in Saccharomyces cerevisiae ) ( Figure 3 ) ( Ciesielski et al, 2016 ; Ciesielski and Craig, 2017 ). Consistent with its structural instability, Isu of S. cerevisiae has a LON/Pim1-dependent fast turnover rate in vivo ( Andrew et al, 2008 ; Song et al, 2012 ).…”

Section: The Client Isu/iscu the Scaffold For Biogenesis Of Fes Clustersmentioning

confidence: 99%

Interaction of client—the scaffold on which FeS clusters are build—with J-domain protein Hsc20 and its evolving Hsp70 partners

Marszałek

Craig

2022

Front. Mol. Biosci.

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In cells molecular chaperone systems consisting of Hsp70 and its obligatory J-domain protein (JDP) co-chaperones transiently interact with a myriad of client proteins—with JDPs typically recruiting their partner Hsp70 to interact with particular clients. The fundamentals of this cyclical interactions between JDP/Hsp70 systems and clients are well established. Much less is known about other aspects of JDP/Hsp70 system function, including how such systems evolved over time. Here we discuss the JDP/Hsp70 system involved in the biogenesis of iron-sulfur (FeS) clusters. Interaction between the client protein, the scaffold on which clusters are built, and its specialized JDP Hsc20 has stayed constant. However, the system’s Hsp70 has changed at least twice. In some species Hsc20’s Hsp70 partner interacts only with the scaffold, in others it has many JDP partners in addition to Hsc20 and interacts with many client proteins. Analysis of this switching of Hsp70 partners has provided insight into the insulation of JDP/Hsp70 systems from one another that can occur when more than one Hsp70 is present in a cellular compartment, as well as how competition among JDPs is balanced when an Hsp70 partner is shared amongst a number of JDPs. Of particularly broad relevance, even though the scaffold’s interactions with Hsc20 and Hsp70 are functionally critical for the biogenesis of FeS cluster-containing proteins, it is the modulation of the Hsc20-Hsp70 interaction per se that allows Hsc20 to function with such different Hsp70 partners.

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Posttranslational control of the scaffold for Fe–S cluster biogenesis as a compensatory regulatory mechanism

Cited by 6 publications

References 36 publications

Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation

Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation

Respiratory chain supercomplexes associate with the cysteine desulfurase complex of the iron–sulfur cluster assembly machinery

Interaction of client—the scaffold on which FeS clusters are build—with J-domain protein Hsc20 and its evolving Hsp70 partners

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