Neuronal JNK pathway activation by IL-1 is mediated through IL1RAPL1, a protein required for development of cognitive functions

Abstract

Interleukin-1-Receptor Accessory Protein Like 1 (IL1RAPL1) gene mutations are associated to cognitive impairment ranging from non-syndromic X-linked mental retardation to autism. Functionally IL1RAPL1 belongs to a novel family of Toll/IL-1 Receptors, but its ligand is unknown. In a recent study, we have shown that IL1RAPL1 is present in dendritic spine where it interacts with PSD-95, a major scaffold protein of excitatory post-synaptic density. We demonstrated that IL1RAPL1 regulates the synaptic localization of PSD-95 by controlling JNK (c-Jun terminal Kinase) activity and PSD-95 phosphorylation. Loss of IL1RAPL1 in mouse not only led to a reduction of excitatory synapses but also to specific deficits in hippocampal long-term synaptic plasticity. Here we report that activation of JNK pathway in neurons by Interleukin-1 (IL-1) is mediated by IL1RAPL1. The interaction of IL1RAPL1 with PSD-95 discloses a novel pathophysiological mechanism underlying cognitive impairment associated with alterations of the JNK pathway in response to IL-1 and leading to the mislocalization of PSD-95, that subsequently result in abnormal synaptic organization and function.

Keywords: IL-1 signaling; IL1RAPL1; JNK; PSD-95.

Figure 1

IL-1 response is impaired in IL1RAPL1 KO neurons. Mature neurons in culture were treated with IL1β (concentration: 0.01 µg/µL) or with vehicle (veh.) (saline, 0.1% BSA) during 10 min before protein extraction. Protein samples were processed as described in Pavlowsky et al. The upper panel shows representative immune-blot of JNK (A) or P38 (B) phosphorylation level in each condition for both genotypes. The lower panel shows quantifications of JNK (A, left) and P38 (B, right) phosphorylation level. Bars show mean of pJNK/JNK or pP38/P38 level ± SEM normalized to vehicle condition. Two-tailed t-test, ***p < 0.001, the number of experiment is indicated as n.