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Temporal regulation of MDA5 inactivation by Caspase-3 dependent cleavage of 14-3-3η

Yun-Jui Chan1, Nien-Tzu Liu1, Fu Hsin1

  • 1Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei City, Taiwan.

Plos Pathogens
|June 6, 2024
PubMed

Insights

Viral infections are controlled by the balance between interferon production and virus replication. A cleaved form of 14-3-3η protein, sub-14-3-3η, impairs antiviral immunity by inhibiting type I interferon induction.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • Type I interferon (IFN) induction and viral replication kinetics determine infection outcomes.
  • Chaperone proteins, like 14-3-3η, are crucial for activating pattern recognition receptors (PRRs) and innate antiviral immunity.
  • Previously, 14-3-3η was shown to facilitate MDA5 oligomerization and redistribution for type I IFN induction.

Purpose of the Study:

  • To investigate the role of 14-3-3η cleavage in MDA5-activated signaling.
  • To identify the protease responsible for 14-3-3η cleavage.
  • To determine the function of the cleaved 14-3-3η fragment (sub-14-3-3η) in type I IFN induction and viral infections.

Main Methods:

  • Analysis of 14-3-3η cleavage upon MDA5 activation.
  • Identification of Caspase-3 as the enzyme responsible for cleaving 14-3-3η.
  • Biochemical assays to assess the interaction of full-length and cleaved 14-3-3η with MDA5.
  • Assessment of type I IFN induction by full-length and cleaved 14-3-3η.
  • Observation of sub-14-3-3η accumulation during human coronavirus and enterovirus infections.

Main Results:

  • 14-3-3η is cleaved upon MDA5 activation, generating a C-terminal fragment (sub-14-3-3η).
  • Caspase-3, activated by MDA5-dependent signaling, is essential for this cleavage.
  • Sub-14-3-3η interacts with MDA5 but fails to induce type I IFN, exhibiting opposing functions to full-length 14-3-3η.
  • Accumulation of sub-14-3-3η and Caspase-3 activation occur during coronavirus and enterovirus infections.
  • RNA viruses may exploit this cleavage mechanism to evade antiviral immunity.

Conclusions:

  • Sub-14-3-3η acts as a negative regulator of MDA5-mediated type I IFN production.
  • Viral induction of sub-14-3-3η formation antagonizes antiviral innate immunity.
  • This cleavage mechanism may represent a viral strategy to impair host defense.
  • The formation of sub-14-3-3η could serve as a negative feedback loop to prevent excessive inflammation and maintain homeostasis.

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