RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 11 July 2014; doi:10.1038/nri3718
I N N AT E I M M U N I T Y
Peroxisomes pack a distinct punch RIG-I-like receptors (RLRs) are a family of innate immune receptors that are activated by nucleic acids and promote antiviral immunity through the induction of type I interferons (IFNs). Odendall et al. now report that RLRs also induce the expression of type III IFNs in response to intracellular infection. They show that RLR-mediated induction of type I and type III IFNs is differentially regulated by distinct intracellular organelles, and they identify peroxisomes as a major site of type III IFN expression. Previous work by the authors had shown that the activation of peroxisome-associated mito chondrial antiviral signalling protein (MAVS; an adaptor protein required for RLR signalling) induces the
NPG
induction of type I and type III IFNs is differentially regulated by distinct intracellular organelles
expression of IFN-stimulated genes (ISGs) and an antiviral immune response independently of type I IFNs. It had been unclear how this occurs but in preliminary experiments, the authors found that the activation of peroxisomal MAVS induces ISG expression via a Janus kinase 2 (JAK2)-dependent signalling pathway. Further studies showed that IFNλ1 (a type III IFN) but not IFNβ (a type I IFN) can induce JAK2 phosphorylation, suggesting that peroxisomal RLRs may induce antiviral responses through the upregulation of type III IFN expression. The authors found that the infection of various types of human cells with different viruses or intracellular bacteria promoted the upregulation of both IFNβ and IFNλ1 in a RIG‑Iand MAVS-dependent manner. To further explore the idea that peroxisomal RLRs preferentially induce type III IFNs, they engineered cells in which the expression of MAVS was restricted to either mitochondria or peroxisomes. In response to viral infection, cells in which MAVS was restricted to mitochondria expressed both IFNλ1 and IFNβ but cells with peroxisome-restricted MAVS only expressed IFNλ1. Thus, peroxisomes seem to selectively induce type III IFNs following the activation of the RLR–MAVS pathway. Additional experiments showed that although there are many common regulators of type I and type III IFNs, extracellular signal-regulated kinase (ERK) and IFN-regulatory factor 1 (IRF1) selectively control IFNβ and IFNλ expression,
NATURE REVIEWS | IMMUNOLOGY
respectively, which suggests a mechanism for how differential RLR signalling from mitochondria and peroxisomes is achieved. As the expression of type III IFNs is thought to be particularly important at mucosal surfaces, the authors examined how RLR–MAVS signalling is regulated in a human intestinal epithelial cell line. Interestingly, the process of intestinal epithelial cell differentiation increased the abundance of peroxisomes in the cells, whereas the number of mitochondria was not affected. When intestinal epithelial cells at various stages of differentiation were infected with viruses, the expression of type III IFNs was shown to increase as cells became more differentiated but the expression of type I IFNs remained constant. Therefore, peroxisome biogenesis increases as intestinal epithelial cells differentiate and this seems to bias these cells towards the generation of type III IFNs. Taken together, these data show that type I and type III IFNs are regulated in distinct ways during infection and emphasize the importance of the intracellular microenvironment for the outcome of innate immune receptor signalling. Interestingly, these findings also suggest that different cell types may achieve biased expression of an IFN subtype by altering the abundance of their mitochondria or peroxisomes. Yvonne Bordon ORIGINAL RESEARCH PAPER Odendall, C. et al. Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nature Immunol. http://dx.doi.org/10.1038/ni.2915 (2014)
VOLUME 14 | AUGUST 2014 © 2014 Macmillan Publishers Limited. All rights reserved
I N N AT E I M M U N I T Y
Peroxisomes pack a distinct punch RIG-I-like receptors (RLRs) are a family of innate immune receptors that are activated by nucleic acids and promote antiviral immunity through the induction of type I interferons (IFNs). Odendall et al. now report that RLRs also induce the expression of type III IFNs in response to intracellular infection. They show that RLR-mediated induction of type I and type III IFNs is differentially regulated by distinct intracellular organelles, and they identify peroxisomes as a major site of type III IFN expression. Previous work by the authors had shown that the activation of peroxisome-associated mito chondrial antiviral signalling protein (MAVS; an adaptor protein required for RLR signalling) induces the
NPG
induction of type I and type III IFNs is differentially regulated by distinct intracellular organelles
expression of IFN-stimulated genes (ISGs) and an antiviral immune response independently of type I IFNs. It had been unclear how this occurs but in preliminary experiments, the authors found that the activation of peroxisomal MAVS induces ISG expression via a Janus kinase 2 (JAK2)-dependent signalling pathway. Further studies showed that IFNλ1 (a type III IFN) but not IFNβ (a type I IFN) can induce JAK2 phosphorylation, suggesting that peroxisomal RLRs may induce antiviral responses through the upregulation of type III IFN expression. The authors found that the infection of various types of human cells with different viruses or intracellular bacteria promoted the upregulation of both IFNβ and IFNλ1 in a RIG‑Iand MAVS-dependent manner. To further explore the idea that peroxisomal RLRs preferentially induce type III IFNs, they engineered cells in which the expression of MAVS was restricted to either mitochondria or peroxisomes. In response to viral infection, cells in which MAVS was restricted to mitochondria expressed both IFNλ1 and IFNβ but cells with peroxisome-restricted MAVS only expressed IFNλ1. Thus, peroxisomes seem to selectively induce type III IFNs following the activation of the RLR–MAVS pathway. Additional experiments showed that although there are many common regulators of type I and type III IFNs, extracellular signal-regulated kinase (ERK) and IFN-regulatory factor 1 (IRF1) selectively control IFNβ and IFNλ expression,
NATURE REVIEWS | IMMUNOLOGY
respectively, which suggests a mechanism for how differential RLR signalling from mitochondria and peroxisomes is achieved. As the expression of type III IFNs is thought to be particularly important at mucosal surfaces, the authors examined how RLR–MAVS signalling is regulated in a human intestinal epithelial cell line. Interestingly, the process of intestinal epithelial cell differentiation increased the abundance of peroxisomes in the cells, whereas the number of mitochondria was not affected. When intestinal epithelial cells at various stages of differentiation were infected with viruses, the expression of type III IFNs was shown to increase as cells became more differentiated but the expression of type I IFNs remained constant. Therefore, peroxisome biogenesis increases as intestinal epithelial cells differentiate and this seems to bias these cells towards the generation of type III IFNs. Taken together, these data show that type I and type III IFNs are regulated in distinct ways during infection and emphasize the importance of the intracellular microenvironment for the outcome of innate immune receptor signalling. Interestingly, these findings also suggest that different cell types may achieve biased expression of an IFN subtype by altering the abundance of their mitochondria or peroxisomes. Yvonne Bordon ORIGINAL RESEARCH PAPER Odendall, C. et al. Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nature Immunol. http://dx.doi.org/10.1038/ni.2915 (2014)
VOLUME 14 | AUGUST 2014 © 2014 Macmillan Publishers Limited. All rights reserved
