Abstract
Since the highly conserved exosome complex mediates the degradation and processing of multiple classes of RNAs, it almost certainly controls diverse biological processes. How this post-transcriptional RNA-regulatory machine impacts cell fate decisions and differentiation is poorly understood. Previously, we demonstrated that exosome complex subunits confer an erythroid maturation barricade, and the erythroid transcription factor GATA-1 dismantles the barricade by transcriptionally repressing the cognate genes. While dissecting requirements for the maturation barricade in Mus musculus, we discovered that the exosome complex is a vital determinant of a developmental signaling transition that dictates proliferation/amplification versus differentiation. Exosome complex integrity in erythroid precursor cells ensures Kit receptor tyrosine kinase expression and stem cell factor/Kit signaling, while preventing responsiveness to erythropoietin-instigated signals that promote differentiation. Functioning as a gatekeeper of this developmental signaling transition, the exosome complex controls the massive production of erythroid cells that ensures organismal survival in homeostatic and stress contexts.
Highlights
The highly conserved exosome complex, an RNA-degrading and processing machine, is expressed in all eukaryotic cells (Januszyk and Lima, 2014; Kilchert et al, 2016)
Nine exosome complex subunits form a cylindrical core consisting of the RNA binding subunits Exosc1 (Csl4), Exosc2 (Rrp4) and Exosc3 (Rrp40), which cap a ring formed by Exosc4 (Rrp41), Exosc5 (Rrp46), Exosc6 (Mtr3), Exosc7 (Rrp42), Exosc8 (Rrp43) and Exosc9 (Rrp45) (Liu et al, 2006; Makino et al, 2013; Makino et al, 2015; Wasmuth et al, 2014) (Figure 1A)
We demonstrated that downregulating exosome complex subunits (Exosc8, Exosc9 or Dis3) in murine fetal liver erythroid precursor cells induced erythroid maturation (McIver et al, 2014)
Summary
The highly conserved exosome complex, an RNA-degrading and processing machine, is expressed in all eukaryotic cells (Januszyk and Lima, 2014; Kilchert et al, 2016). Mutations of Exosc (Rrp4) disrupt 5.8S rRNA 3’-end processing (Mitchell et al, 1996). Exosc assembles into a complex with components homologous to bacterial 3’ to 5’ exoribonuclease (PNPase) (Mitchell et al, 1997). Nine exosome complex subunits form a cylindrical core consisting of the RNA binding subunits Exosc (Csl4), Exosc (Rrp4) and Exosc (Rrp40), which cap a ring formed by Exosc (Rrp41), Exosc (Rrp46), Exosc (Mtr3), Exosc (Rrp42), Exosc (Rrp43) and Exosc (Rrp45) (Liu et al, 2006; Makino et al, 2013; Makino et al, 2015; Wasmuth et al, 2014) (Figure 1A). Despite homology with bacterial PNPases, the vertebrate core subunits lack RNA-degrading activity (Liu et al, 2006).
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