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Background <p>Megakaryocytes expand their genomes and secretory capacity to produce platelets, which burden the endoplasmic reticulum (ER) with a high proteostatic load. The role of activating transcription factor 6 (ATF6) in this setting has remained elusive.</p> Objective <p>To define the role of ATF6 in regulating ER proteostasis and megakaryocyte maturation in MEG-01 cells cultured without PMA, and to identify key mediators that relay ATF6-dependent transcriptional and secretory reprogramming.</p> Results <p>Increasing ATF6 levels increased the unfolded protein response activity, ER-associated degradation, N-linked glycosylation, autophagy, AMPK and sirtuin signaling, and DNA repair linked to TP53, while reducing microRNA biogenesis, pre-mRNA processing, and senescence signatures. The knockdown exhibited a reciprocal pattern. Upstream analyses pointed to the restraint of proliferative drivers and support for genomic surveillance. Changes in ATF6 levels are relayed by SNURF and EGR1 to reshape megakaryocyte programs. SNURF and EGR1 function as positive and negative effectors, respectively. SNURF gain-of-function reinforced the unfolded protein response core, canonical megakaryocyte transcription factors, terminal maturation factors, and genes that preserved genome stability and shifted the secretome toward TIMP-1 and osteoprotegerin. EGR1 produced the opposite effects and reweighted interleukin-6, interleukin-1 beta, and interleukin-8. Class I MHC pathways changed in the same direction as the intracellular programs.</p> Conclusion <p>Altogether, these results define an ATF6-centered circuit that links endomitosis, proteostasis, genome integrity, and effector output, and provide a mechanistic rationale to explore whether targeted modulation can improve ex vivo platelet production and adjust thromboinflammatory signaling.</p>

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ATF6 expression governs megakaryocyte maturation through dual regulatory mechanisms

  • 期刊论文

  • 发表日期：

    2026年3月20日

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  • Se-Ryeon Lee,
  • Yu-Seon Lee,
  • Jungsun Kim,
  • Sang Hoon Jeong,
  • Ju-Han Lee,
  • Hwa-Jung Sung,
  • Hong Lee

摘要

Background

Megakaryocytes expand their genomes and secretory capacity to produce platelets, which burden the endoplasmic reticulum (ER) with a high proteostatic load. The role of activating transcription factor 6 (ATF6) in this setting has remained elusive.

Objective

To define the role of ATF6 in regulating ER proteostasis and megakaryocyte maturation in MEG-01 cells cultured without PMA, and to identify key mediators that relay ATF6-dependent transcriptional and secretory reprogramming.

Results

Increasing ATF6 levels increased the unfolded protein response activity, ER-associated degradation, N-linked glycosylation, autophagy, AMPK and sirtuin signaling, and DNA repair linked to TP53, while reducing microRNA biogenesis, pre-mRNA processing, and senescence signatures. The knockdown exhibited a reciprocal pattern. Upstream analyses pointed to the restraint of proliferative drivers and support for genomic surveillance. Changes in ATF6 levels are relayed by SNURF and EGR1 to reshape megakaryocyte programs. SNURF and EGR1 function as positive and negative effectors, respectively. SNURF gain-of-function reinforced the unfolded protein response core, canonical megakaryocyte transcription factors, terminal maturation factors, and genes that preserved genome stability and shifted the secretome toward TIMP-1 and osteoprotegerin. EGR1 produced the opposite effects and reweighted interleukin-6, interleukin-1 beta, and interleukin-8. Class I MHC pathways changed in the same direction as the intracellular programs.

Conclusion

Altogether, these results define an ATF6-centered circuit that links endomitosis, proteostasis, genome integrity, and effector output, and provide a mechanistic rationale to explore whether targeted modulation can improve ex vivo platelet production and adjust thromboinflammatory signaling.