Y705 and S727 are required for mitochondrial import and transcriptional activities of STAT3 and regulate proliferation of embryonic and tissue stem cells

The STAT3 transcription factor, acting both in the nucleus and mitochondria, maintains embryonic stem cell pluripotency and promotes their proliferation. In this work, using zebrafish, we determined in vivo that mitochondrial STAT3 regulates mtDNA transcription in embryonic and larval stem cell niches and that this activity affects their proliferation rates. As a result, we demonstrated that STAT3 import inside mitochondria requires Y705 phosphorylation by Jak, while its mitochondrial transcriptional activity, as well as its effect on proliferation, depends on the MAPK target S727. These data were confirmed using mouse embryonic stem cells: while the Y705 mutated STAT3 cannot enter mitochondria, the S727 mutation does not affect the import in the organelle and is responsible for STAT3-dependent mitochondrial transcription. Surprisingly, STAT3-dependent increase of mitochondrial transcription seems independent from STAT3 binding to STAT3 responsive elements. Finally, loss of function experiments, with chemical inhibition of the JAK/STAT3 pathway or genetic ablation of stat3 gene, demonstrated that STAT3 is also required for cell proliferation in the intestine of zebrafish.

Correction to: ZFP281 recruits polycomb repressive complex 2 to restrict extraembryonic endoderm potential in safeguarding embryonic stem cell pluripotency

In the original publication the labelling in middle and bottom panels of figure 2k is published incorrectly as “Soc17”. The correct labeling is available in this correction as “Sox17”.

Mitochondrial STAT3 regulates proliferation of tissue stem cells

ABSTRACTThe STAT3 transcription factor, acting both in the nucleus and mitochondria, maintains embryonic stem cell pluripotency and promotes their proliferation. In this work, using zebrafish, we determined in vivo that mitochondrial STAT3 regulates mtDNA transcription in embryonic and larval stem cell niches and that this activity determines their proliferation rates. To dissect the molecular requirements for mitochondrial STAT3 functions, we used drugs and missense mutations to kinase-targeted STAT3 residues. As a result, we demonstrated that STAT3 import inside mitochondria requires Y705 phosphorylation by Jak2, while its mitochondrial transcriptional activity, as well as its effect on proliferation, depends on the MAPK target S727. Moreover, while STAT3-dependent mtDNA transcription is needed and sufficient to induce cell proliferation, it is not required to maintain a stem-like phenotype in the tectal niche. Surprisingly, STAT3-dependent increase of mitochondrial transcription seems independent from STAT3 binding to DNA and does not originate from STAT3 regulation of mtDNA replication.