title: The X-linked intellectual disability protein IL1RAPL1 regulates excitatory synapse formation by binding PTPδ and RhoGAP2.
abstract: Mutations of the Interleukin-1-receptor accessory protein like 1 (IL1RAPL1) gene are associated with cognitive impairment ranging from non-syndromic X-linked mental retardation to autism. IL1RAPL1 belongs to a novel family of IL1/Toll receptors, which is localized at excitatory synapses and interacts with PSD-95. We previously showed that IL1RAPL1 regulates the synaptic localization of PSD-95 by controlling c-Jun N-terminal kinase activity and PSD-95 phosphorylation. Here, we show that the IgG-like extracellular domains of IL1RAPL1 induce excitatory pre-synapse formation by interacting with protein tyrosine phosphatase delta (PTPδ). We also found that IL1RAPL1 TIR domains interact with RhoGAP2, which is localized at the excitatory post-synaptic density. More interestingly, the IL1RAPL1/PTPδ complex recruits RhoGAP2 at excitatory synapses to induce dendritic spine formation. We also found that the IL1RAPL1 paralog, IL1RAPL2, interacts with PTPδ and induces excitatory synapse and dendritic spine formation. The interaction of the IL1RAPL1 family of proteins with PTPδ and RhoGAP2 reveals a pathophysiological mechanism of cognitive impairment associated with a novel type of trans-synaptic signaling that regulates excitatory synapse and dendritic spine formation.
authors.affiliation: CNR Institute of Neuroscience, Department of Pharmacology, University of Milan, 20129 Milan, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Valnegri
authors.forename: Chiara
authors.initials: C
authors.lastname: Montrasio
authors.forename: Dario
authors.initials: D
authors.lastname: Brambilla
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
mesh_terms: D000818:Animals; D019556:COS Cells; D020848:Chimerin 1 / Q000378:metabolism*; D002522:Chlorocebus aethiops; D016000:Cluster Analysis; D049229:Dendritic Spines / Q000378:metabolism; D050172:Genes, X-Linked; D057809:HEK293 Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D053577:Interleukin-1 Receptor Accessory Protein / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D020848:Chimerin 1; C407643:IL1RAPL1 protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2