DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression.

Article Details

Citation

Mukhopadhyay R, Ray PS, Arif A, Brady AK, Kinter M, Fox PL

DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression.

Mol Cell. 2008 Nov 7;32(3):371-82. doi: 10.1016/j.molcel.2008.09.019.

PubMed ID
18995835 [ View in PubMed
]
Abstract

Phosphorylation of ribosomal protein L13a is essential for translational repression of inflammatory genes by the interferon (IFN)-gamma-activated inhibitor of translation (GAIT) complex. Here we show that IFN-gamma activates a kinase cascade in which death-associated protein kinase-1 (DAPK) activates zipper-interacting protein kinase (ZIPK), culminating in L13a phosphorylation on Ser(77), L13a release from the ribosome, and translational silencing of GAIT element-bearing target mRNAs. Remarkably, both kinase mRNAs contain functional 3'UTR GAIT elements, and thus the same inhibitory pathway activated by the kinases is co-opted to suppress their expression. Inhibition of DAPK and ZIPK facilitates cell restoration to the basal state and allows renewed induction of GAIT target transcripts by repeated stimulation. Thus, the DAPK-ZIPK-L13a axis forms a unique regulatory module that first represses, then repermits inflammatory gene expression. We propose that the module presents an important checkpoint in the macrophage "resolution of inflammation" program, and that pathway defects may contribute to chronic inflammatory disorders.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Death-associated protein kinase 1P53355Details
Death-associated protein kinase 3O43293Details
60S ribosomal protein L13aP40429Details