Noncanonical IFN Signaling, Steroids, and STATs: A Probable Role of V-ATPase

Figure 1

Nuclear receptor signaling as the template for IFN signaling via the JAK/STAT pathway. (a) Steroid hormones such as estrogen and dihydrotestosterone nuclear receptor ligands (NL) signal through cytoplasmic soluble nuclear receptors (NRs). NR signaling involves scaffolding proteins called steroid receptor coactivators (SRC) which serve as the platform for other factors such as histone acetyltransferases (CBP/p300) and kinases as well as other players such as a mediator complex consisting of 26 or more protein subunits. These factors are present at both the promoter and enhancer of genes specifically activated by steroids and their receptors. Specific transcription occurs at both the promoter (mRNA) and enhancer (eRNA) by RNA polymerase II. (b) We have shown that interferon (IFN) signaling involves the presence of IFNγ, IFNγ receptor, activated JAKs, activated STATs, and transferases at the promoters of genes activated by IFNs. It is predicted that similar players are present at the relevant enhancer of genes activated by IFNs, a prediction that can readily be tested. Adherents of the canonical model of IFN signaling do not conceptually accept retrograde trafficking of plasma membrane receptors to the nucleus, although this has been widely shown in JAK/STAT signaling as well as in receptor tyrosine kinase signaling (see text).

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