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Threonyl-tRNA synthetase activates STAT3 by a nontranslational mechanism
Pallob Barai1, Reean Abdullah1, Shruti V Bendre2
1Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Abstract:
Signal transducer and activator of transcription 3 (STAT3) is a major regulator of cell proliferation and survival, often found to be aberrantly activated in cancer. Here, we identify threonyl-tRNA synthetase 1 (TARS1) as an activator of STAT3. Elevated TARS1 expression in lung cancer correlates with poor patient survival. We find that overexpression of TARS1 supports non-small cell lung cancer cell proliferation in vitro, tumor formation of xenografts in mice, and hyperactivity of STAT3. Catalytically inactive TARS1 promotes STAT3 activation and cell proliferation, indicating that TARS1 functions in a nontranslational manner. Mechanistically, TARS1 physically associates with both STAT3 and Janus kinase (JAK), and TARS1 activation of STAT3 requires basal JAK activity. We propose a scaffold model in which TARS1 promotes proximity of STAT3 to JAK and subsequent phosphorylation of STAT3. This model is supported by the results of reconstitution experiments expressing recombinant TARS1, STAT3, and JAK1 in noncancer cells. Our study uncovers a novel mechanism of STAT3 dysregulation in cancer and provides a strong basis for therapeutic targeting of the noncanonical function of a housekeeping protein.
Insights
Signal transducer and activator of transcription 3 (STAT3) is activated by threonyl-tRNA synthetase 1 (TARS1), a protein linked to poor lung cancer survival. TARS1 acts as a scaffold, bringing STAT3 and JAK together to promote cancer cell proliferation.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- Signal transducer and activator of transcription 3 (STAT3) is a key regulator of cell growth and survival, frequently dysregulated in various cancers.
- Aberrant STAT3 activation is a hallmark of many malignancies, driving tumor progression and resistance to therapy.
Purpose of the Study:
- To identify novel regulators of STAT3 activation in cancer.
- To investigate the role of threonyl-tRNA synthetase 1 (TARS1) in STAT3 signaling and non-small cell lung cancer (NSCLC).
Main Methods:
- Correlation analysis of TARS1 expression with patient survival in lung cancer.
- In vitro studies assessing the impact of TARS1 overexpression on NSCLC cell proliferation.
- In vivo xenograft mouse models to evaluate TARS1's effect on tumor formation.
- Biochemical assays to determine the interaction between TARS1, STAT3, and Janus kinase (JAK).
- Reconstitution experiments in non-cancer cells.
Main Results:
- Elevated TARS1 expression in lung cancer correlates with reduced patient survival.
- Overexpression of TARS1 enhances NSCLC cell proliferation, xenograft tumor growth, and STAT3 hyperactivity.
- Catalytically inactive TARS1 retains its ability to activate STAT3 and promote cell proliferation, suggesting a non-translational function.
- TARS1 physically interacts with STAT3 and JAK, requiring basal JAK activity for STAT3 activation.
- A scaffold model is proposed where TARS1 facilitates STAT3-JAK proximity, leading to STAT3 phosphorylation.
Conclusions:
- TARS1 is a novel non-canonical activator of STAT3 in cancer.
- TARS1's scaffolding function promotes STAT3-mediated cell proliferation and tumor growth.
- Targeting the non-translational role of TARS1 presents a potential therapeutic strategy for lung cancer.
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