Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms

Abstract

Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation.

Simultaneous Detection of mRNA and Protein in Single Cells Using Immunofluorescence-Combined Single-Molecule RNA FISH

“…We were able to clearly see co-localization of the MCPIP1 protein with the IL6 transcript (Figure 4D, white arrows). These observations further reinforce the data presented by Mino et al showing binding of MCPIP1 to IL-6 mRNA and degradation of this transcript (19). An intensity line profile illustrates co-localization observed in the boxed area in more detail (Figure 4, E and F).…”

Posttranscriptional T cell gene regulation to limit Tfh cells and autoimmunity

“…Varying levels of regulation of Regnase-1 and Roquin may fine tune target repression [67 ]. Indeed, although Regnase-1 and Roquin target similar mRNAs, Regnase-1 operates in the ribosomes and endoplasmic reticulum together with the helicase UPF1 to degrade translationally active mRNAs during the early phase of inflammation, whereas Roquin functions in Pbodies and stress granules to degrade translationally-inactive mRNAs [68 ] (Figure 1). It is therefore unsurprising that Regnase-1 À/À mice have a similar phenotype to the sanroque mouse: splenomegaly, lymphadenopathy, activated T cells with strong ANAs and multi-organ plasma cell infiltration [69].…”

Monocyte Chemotactic Protein-induced Protein 1 and 4 Form a Complex but Act Independently in Regulation of Interleukin-6 mRNA Degradation

“…The mRNA targets of MCPIP1 nuclease are now expanding to c-Rel, IL-2, ICOS, Ox40, TNFR2, GATA3, and MCPIP1 self mRNA (13,15,16). MCPIP1 promotes their degradation by targeting their 3Ј-untranslated region (3Ј-UTR) (10,13). MCPIP1 specifically recognized a stem-loop structure on the 3Ј-UTR of its substrate mRNAs (10).…”

“…MCPIP1 promotes their degradation by targeting their 3Ј-untranslated region (3Ј-UTR) (10,13). MCPIP1 specifically recognized a stem-loop structure on the 3Ј-UTR of its substrate mRNAs (10).…”

“…For example, tristetraprolin, Roquin, and ZAP are well-studied CCCH-zinc finger-containing proteins that target mRNA degradation through different mechanisms (4 -9). MCPIP1 is an endonuclease and selectively destabilizes mRNAs that encode certain inflammatory cytokines such as IL-6 and IL-12 (2,10). Through this central mechanism, MCPIP1 serves as an essential regulator in inflammatory cell activation and immune homeostasis (2).…”