A STAT3 protein complex required for mitochondrial mRNA stability and cancer

Area of Science:

• Mitochondrial biology
• Molecular oncology
• Gene regulation

Background:

• Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor implicated in various diseases, including cancer.
• A non-transcriptional role of STAT3 in mitochondria is essential for tissue function and tumorigenesis, but its mechanism was unclear.

Purpose of the Study:

• To elucidate the mechanism behind mitochondrial STAT3 activity.
• To identify novel therapeutic targets for STAT3-driven cancers.

Main Methods:

• Immunoprecipitation and mass spectrometry were employed to identify protein complexes involving STAT3.
• Analysis of STAT3 complex enrichment in lung adenocarcinoma patient samples.
• In vivo studies to assess the impact of complex deletion on tumor growth.

Main Results:

• A novel complex comprising STAT3, LRPPRC, and SLIRP was identified.
• This complex is critical for the stability and mitochondrial ribosomal transport of mitochondrially encoded mRNAs.
• The STAT3-LRPPRC-SLIRP complex is enriched in lung adenocarcinoma and its inhibition suppresses tumor growth in vivo.

Conclusions:

• Mitochondrial STAT3 functions through a complex with LRPPRC and SLIRP to regulate mitochondrial gene expression.
• Targeting this complex presents a promising therapeutic strategy for lung adenocarcinoma by inhibiting mitochondrial STAT3 activity.