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MARK2 phosphorylates eIF2α in response to proteotoxic stress.

Yu-Ning Lu1,2, Sarah Kavianpour1,2, Tao Zhang1,2

  • 1Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.

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|March 11, 2021
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Researchers discovered a new pathway regulating protein synthesis during cellular stress. This pathway involves protein kinase C delta (PKCδ) activating microtubule affinity-regulating kinase 2 (MARK2), which then phosphorylates eukaryotic initiation factor 2 alpha (eIF2α).

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Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Neuroscience

Background:

  • Protein synthesis regulation is crucial for cellular homeostasis and preventing disease.
  • Phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) is a key step in translation control.
  • Dysregulation of this process is linked to various human diseases.

Purpose of the Study:

  • To identify novel kinases involved in eIF2α phosphorylation during proteotoxic stress.
  • To elucidate the signaling cascade regulating eIF2α phosphorylation in response to cellular stress.
  • To investigate the role of this pathway in neurodegenerative diseases.

Main Methods:

  • Identification of direct eIF2α kinases using cellular and biochemical assays.
  • Confirmation of MARK2 activity in cells lacking known eIF2α kinases.
  • Investigation of MARK2 regulation by protein kinase C delta (PKCδ) and heat shock protein 90 (HSP90).
  • Analysis of MARK2 and PKCδ activation in mouse models of neurodegeneration and human ALS patients.

Main Results:

  • Microtubule affinity-regulating kinase 2 (MARK2) was identified as a direct kinase of eIF2α, activated by proteotoxic stress.
  • MARK2 functions independently of the four previously known eIF2α kinases.
  • Protein kinase C delta (PKCδ) directly phosphorylates and activates MARK2, sensing proteotoxic stress via HSP90 interaction.
  • Both MARK2 and PKCδ are activated in neurodegenerative models and ALS patient samples.

Conclusions:

  • A novel PKCδ-MARK2-eIF2α signaling cascade is identified, critical for cellular proteotoxic stress response.
  • This pathway represents a potential therapeutic target for diseases associated with protein misfolding and neurodegeneration, such as ALS.