QUAKING Regulates Microexon Alternative Splicing of the Rho GTPase Pathway and Controls Microglia Homeostasis

Cell Rep. 2020 Dec 29;33(13):108560. doi: 10.1016/j.celrep.2020.108560.

Abstract

The role of RNA binding proteins in regulating the phagocytic and cytokine-releasing functions of microglia is unknown. Here, we show that microglia deficient for the QUAKING (QKI) RNA binding protein have increased proinflammatory cytokine release and defects in processing phagocytosed cargo. Splicing analysis reveals a role for QKI in regulating microexon networks of the Rho GTPase pathway. We show an increase in RhoA activation and proinflammatory cytokines in QKI-deficient microglia that are repressed by treating with a Rock kinase inhibitor. During the cuprizone diet, mice with QKI-deficient microglia are inefficient at supporting central nervous system (CNS) remyelination and cause the recruited oligodendrocyte precursor cells to undergo apoptosis. Furthermore, the expression of QKI in microglia is downregulated in preactive, chronic active, and remyelinating white matter lesions of multiple sclerosis (MS) patients. Overall, our findings identify QKI as an alternative splicing regulator governing a network of Rho GTPase microexons with implications for CNS remyelination and MS patients.

Keywords: QKI; Rho GTPase, RNA-binding protein, QUAKING, phagocytosis; alternative splicing; microexons; microglia; myelination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Cells, Cultured
  • Central Nervous System / metabolism
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation*
  • Homeostasis
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / cytology
  • Microglia / physiology*
  • Multiple Sclerosis / genetics
  • Phagocytosis
  • RNA / metabolism
  • RNA-Binding Proteins / physiology*
  • RNA-Seq
  • Remyelination
  • Signal Transduction / drug effects
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / genetics*
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Cytokines
  • Qk protein, mouse
  • RNA-Binding Proteins
  • RNA-binding protein QKI-5, human
  • RNA
  • Rock2 protein, mouse
  • rho-Associated Kinases
  • RhoA protein, mouse
  • rhoA GTP-Binding Protein

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