A Central Nervous System-Dependent Intron-Embedded Gene Encodes a Novel Murine Fyn Binding Protein.

Noureddine Ben Khalaf,Safa Taha,Moiz Bakhiet,M Dahmani Fathallah,Jung Weon Lee

doi:10.1371/journal.pone.0149612

Abstract

The interplay between the nervous and immune systems is gradually being unraveled. We previously reported in the mouse the novel soluble immune system factor ISRAA, whose activation in the spleen is central nervous system-dependent. We also showed that ISRAA plays a role in modulating anti-infection immunity. Herein, we report the genomic description of the israa locus, along with some insights into the structure-function relationship of the protein. Our findings revealed that israa is nested within intron 6 of the mouse zmiz1 gene. Protein sequence analysis revealed a typical SH2 binding motif (Y102TEV), with Fyn being the most likely binding partner. Docking simulation showed a favorable conformation for the ISRAA-Fyn complex, with a specific binding mode for the binding of the YTEV motif to the SH2 domain. Experimental studies showed that in vitro, recombinant ISRAA is phosphorylated by Fyn at tyrosine 102. Cell transfection and pull-down experiments revealed Fyn as a binding partner of ISRAA in the EL4 mouse T-cell line. Indeed, we demonstrated that ISRAA downregulates T-cell activation and the phosphorylation of an activation tyrosine (Y416) of Src-family kinases in mouse splenocytes. Our observations highlight ISRAA as a novel Fyn binding protein that is likely to be involved in a signaling pathway driven by the nervous system.

Highlights

The nervous and immune systems have long been considered to be separate compartments that fulfill different functions, but recent studies showed the existence of a mutual interaction between the two systems in both physiological and pathological conditions
Ensembl Blast analysis showed that israa is a 2,093 bp gene embedded within intron 6 of the zmiz1 gene on mouse chromosome 14 (Fig 1A). zmiz1 encodes a 1,072 amino acid protein: the zinc finger, MIZ-type containing 1 protein (NP_899031.2), which is known as zimp10 and is located in region 14qa3 of mouse chromosome 14
Israa has been identified in mice and described as a novel immune system modulator whose transcription is activated in vivo in a manner dependent on intact splenic innervations

Summary

Introduction

The nervous and immune systems have long been considered to be separate compartments that fulfill different functions, but recent studies showed the existence of a mutual interaction between the two systems in both physiological and pathological conditions. Cytokines released by immune cells are able to signal to the brain the occurrence of infections [1, 2] by directly accessing the CNS [3] or by stimulating afferent neurons [4]. In response to environmental changes, the brain can modulate immune system functions and maintain homeostasis through a network of neurotransmitters and specific receptors expressed on immune cells [5]. The modulation of immune functions by the CNS occurs in different ways: the autonomic nervous system, the catecholaminergic pathway, or neuropeptide and hormone release [6]. In the PLOS ONE | DOI:10.1371/journal.pone.0149612 February 22, 2016

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