CYFIP1 overexpression amplifies IL-6/STAT3 and IFN-γ/STAT1 signaling: potential implications for neuroinflammation and autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) encompasses a group of neurodevelopmental disorders characterised by impaired social interaction, delayed language development, and repetitive or restrictive behaviours. While both genetic and environmental factors contribute to ASD, the specific molecular mechanisms underlying these interactions remain unclear. In a recent preprint, we showed that cytokine signaling may be dysregulated in chromosome 15q-duplication syndrome (Dup(15q)), one of the most common syndromic forms of ASD. Specifically, Dup(15q) induced pluripotent stem cells (iPSC)-derived neurons exhibit an amplified Signal Transducer and Activator of Transcription-3 (STAT3) response to Interleukin-6 (IL-6), a proinflammatory cytokine often upregulated in ASD. To identify which gene in the 15q region may be responsible for modifying cytokine signalling responses in Dup(15q), we focus on the Cytoplasmic FMRP-Interacting Protein 1 (CYFIP1) gene, as increased CYFIP1 dosage in Dup(15q) is associated with increased severity of neurobehavioral symptoms in individuals with Dup(15q) and CYFIP1 dysregulation has been linked to altered expression of various genes involved in immunoregulatory signalling pathways. Here, we explore the eeects of CYFIP1 overexpression (CYFIP1-OE) on cytokine signaling, demonstrating that CYFIP1-OE in HEK293 cells modifies the expression and activity of several cytokine signaling-related transcription factors, including STAT3 and STAT1. Additionally, we use SH-SY5Y neuroblastoma cells to assess neuron-related phenotypes, showing that CYFIP1-OE alters IL-6-induced neurite outgrowth. These findings provide novel insights into how CYFIP1 may contribute to dysregulated cytokine responses in ASD, advancing our understanding of the molecular mechanisms that underlie neuroinflammatory processes in this disorder.