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The role of ISCA proteins in the biogenesis of Iron-Sulfur proteins now better understood

ISCA1 is essential for mitochondrial Fe4S4 biogenesis in vivo.

Beilschmidt LK(1,)(2,)(3,)(4,)(5), Ollagnier de Choudens S(6,)(7,)(8), Fournier M(1,)(2,)(3,)(4), Sanakis I(9), Hograindleur MA(6,)(7,)(8,)(10), Clemancey M(7,)(8,)(10), Blondin G(7,)(8,)(10), Schmucker S(1,)(2,)(3,)(4,)(5), Eisenmann A(1,)(2,)(3,)(4,)(5), Weiss A(1,)(2,)(3,)(4), Koebel P(1,)(2,)(3,)(4), Messaddeq N(1,)(2,)(3,)(4), Puccio H(1,)(2,)(3,)(4,)(5), Martelli A(1,)(2,)(3,)(4,)(5).

Nat Commun May 11, 2017

May 11, 2017

The biogenesis of iron-sulfur clusters and their transfer to acceptor proteins is a very complex process and the molecular details of this synthesis is still poorly understood. Many molecules are involved in the assembly of Iron-Sulfur clusters and their dysfunction is linked to many rare genetic diseases. The team of Hélène Puccio has just published the results of its investigations carried out on the proteins ISCA1 and ISCA2, partly lifting the veil on their respective roles in this canonical process. These results are published on May 11th in the journal Nature communications.


Role and origin of Fe-S clusters
The iron-sulfur (Fe-S) clusters are co-factors containing iron atoms (usually 2, 3 or 4 atoms) and sulfur. Capable of loading and unloading, these molecules naturally trigger electron exchanges and thus participate in many biological processes. They may also be included in the structure of Fe-S proteins. Initially known for their involvement in the respiratory chain and the Krebs cycle, current research shows that their function far exceeds these processes since they also appear to be involved in the regulation of gene expression.

Roles of ISCA1 and ISCA2 proteins
Hélène Puccio's team has been interested in the mammalian ISCA1 and ISCA2 proteins, proteins very similar that are involved in the biogenesis of Fe-S proteins but whose precise role was unclear. After purification, the researchers first showed that both proteins contained Fe-S clusters (Fe2S2). However, biochemical analysis revealed that both proteins had very different properties, in particular in terms of oxidation-reduction, suggesting that their mechanisms of action might not be identical. Similarly, the study of their interactions with other actors in the biosynthesis of Fe-S proteins showed that, although they can form a complex, they also interacted specifically with different proteins throughout the process.

While previous studies on bacteria or HeLa cells indicated a similar or even redundant role for both proteins, the researchers separately suppressed the ISCA1 and ISCA2 genes in mouse muscles, causing in vivo a decrease in Fe4S4 proteins in the case of ISCA1 inactivation, but not in the case of ISCA2 inactivation. Furthermore, their data indicate that ISCA2 is unable to compensate for the absence of ISCA1, demonstrating non-redundant and non-overlapping function.

The role of ISCA1 as a "distributing" protein that brings Fe-S clusters to "acceptor" proteins is confirmed. Its precise spatio-temporal involvement in the Fe-S protein biosynthesis pathway has been clarified, designating it as an indispensable actor for the maturation of Fe4S4 proteins within the mitochondria. The role of ISCA2, although associated to a severe congenital diseases of neuronal development, is not yet elucidated. Its function is most likely important during embryonic development.


The study was funded by the Friedreich Ataxia Research Alliance (FARA), the French Agence National pour la recherche (ANR) and the European Research Council (ERC).

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