A genome-wide RNAi screen identifies MASK as a positive regulator of cytokine receptor stability

J Cell Sci. 2018 Jul 6;131(13):jcs209551. doi: 10.1242/jcs.209551.

Abstract

Cytokine receptors often act via the Janus kinase and signal transducer and activator of transcription (JAK/STAT) pathway to form a signalling cascade that is essential for processes such as haematopoiesis, immune responses and tissue homeostasis. In order to transduce ligand activation, cytokine receptors must dimerise. However, mechanisms regulating their dimerisation are poorly understood. In order to better understand the processes regulating cytokine receptor levels, and their activity and dimerisation, we analysed the highly conserved JAK/STAT pathway in Drosophila, which acts via a single receptor, known as Domeless. We performed a genome-wide RNAi screen in Drosophila cells, identifying MASK as a positive regulator of Domeless dimerisation and protein levels. We show that MASK is able to regulate receptor levels and JAK/STAT signalling both in vitro and in vivo We also show that its human homologue, ANKHD1, is also able to regulate JAK/STAT signalling and the levels of a subset of pathway receptors in human cells. Taken together, our results identify MASK as a novel regulator of cytokine receptor levels, and suggest functional conservation, which may have implications for human health.This article has an associated First Person interview with the first author of the paper.

Keywords: ANKYRIN domain; Cytokine receptor; Dimerisation; JAK/STAT; RNAi.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Drosophila Proteins / chemistry*
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Gene Expression Regulation
  • Genome, Insect*
  • Humans
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Protein Binding
  • Protein Stability
  • RNA Interference*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Receptors, Cytokine / genetics*
  • Receptors, Cytokine / metabolism
  • Receptors, Interleukin / chemistry*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism
  • Signal Transduction

Substances

  • ANKHD1 protein, human
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Mask protein, Drosophila
  • RNA-Binding Proteins
  • Receptors, Cytokine
  • Receptors, Interleukin
  • STAT Transcription Factors
  • dome protein, Drosophila
  • Janus Kinases