Metastable biomolecular condensates of interferon-inducible antiviral Mx-family GTPases: A paradigm shift in the last three years
Membraneless organelles (MLOs) in the cytoplasm and nucleus in the form of phase-separated biomolecularcondensates are increasingly viewed as critical in regulating diverse cellular functions.We summarize a paradigmshift over the last 3 years in the field of interferon (IFN)-inducible antiviral Mx-family GTPases. Expression of the
‘myxovirus resistance proteins’ MxA in human cells and its ortholog Mx1 in murine cells is increased 50- to100-fold by Type I (IFN-alpha and -beta) and III IFNs (IFN-lambda). Human MxA forms cytoplasmic structures, while murineMx1 forms nuclear bodies. Since 2002, it has been widely thought that human (Hu) MxA is associated with themembraneous smooth endoplasmic reticulum (ER). In a paradigm shift, our recent data showed that HuMxAformed membraneless phase-separated biomolecular condensates in the cytoplasm. Some of the HuMxA condensatesadhered to intermediate filaments generating a reticular pattern. Murine (Mu) Mx1, which was predominantlynuclear, was also confirmed to be in phase-separated nuclear biomolecular condensates. A subset ofHuh7 cells showed association of GFP-MuMx1 with intermediate filaments in the cytoplasm. While cells withcytoplasmic GFP-HuMxA condensates and cytoplasmic GFP-MuMx1 filaments showed an antiviral phenotypetowards vesicular stomatitis virus (VSV), those with only nuclear GFP-MuMx1 bodies did not. The new databring forward the paradigm that both human MxA and murine Mx1 give rise to phase-separated biomolecularcondensates, albeit in different subcellular compartments, and that differences in the subcellular localization ofcondensates of different Mx proteins determines the spectrum of their antiviral activity.
Volume 46, 2021
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