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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

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Viral M45 and necroptosis-associated proteins form heteromeric amyloid assemblies

Chi Ll Pham1, Nirukshan Shanmugam1, Merryn Strange1

  • 1Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine and Health and Sydney Nano, University of Sydney, Sydney, NSW, Australia.

EMBO Reports
|December 1, 2018
PubMed

Insights

Murine cytomegalovirus protein M45

Area of Science:

  • Virology
  • Immunology
  • Cellular Biology

Background:

  • Necroptosis is a regulated form of cell death.
  • Tumor necrosis factor receptor (TNFR) activation can trigger necroptosis.
  • Murine cytomegalovirus (MCMV) protein M45 inhibits necroptosis.

Purpose of the Study:

  • To investigate the mechanism by which MCMV protein M45 inhibits necroptosis.
  • To identify the M45 protein region responsible for necroptosis inhibition.
  • To elucidate the interaction of M45 with host cell necroptosis machinery.

Main Methods:

  • Protein truncation and mutagenesis of MCMV M45.
  • In vitro amyloid fibril formation assays.
  • Analysis of M45 interactions with RIPK1, RIPK3, and ZBP1.

Main Results:

  • The N-terminal 90 residues of M45, containing a RIP homotypic interaction motif (RHIM), are sufficient for inhibiting necroptosis.
  • M45's N-terminal region self-assembles into amyloid fibrils.
  • M45 RHIM interacts with RIPK1, RIPK3, and ZBP1 RHIMs, forming heteromeric amyloid structures.
  • M45 RHIM mutations disrupt amyloid formation and necroptosis inhibition.
  • M45 preferentially interacts with RIPK3 and ZBP1, altering host RHIM protein assemblies.

Conclusions:

  • The amyloidogenic nature of the M45 RHIM is crucial for its necroptosis inhibitory function.
  • M45 mimics RIPK1 or ZBP1 interactions with RIPK3 by forming heteromeric amyloid structures.
  • This mechanism explains how M45 inhibits necroptosis.
Keywords:
M45RIP homotypic interaction motifRIPK3amyloidnecroptosis

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