Novel FMRP interaction networks linked to cellular stress

Abstract

Silencing of the fragile X mental retardation 1 (FMR1) gene and consequently lack of synthesis of FMR protein (FMRP) are associated with fragile X syndrome, which is one of the most prevalent inherited intellectual disabilities, with additional roles in increased viral infection, liver disease, and reduced cancer risk. FMRP plays critical roles in chromatin dynamics, RNA binding, mRNA transport, and mRNA translation. However, the underlying molecular mechanisms, including the (sub)cellular FMRP protein networks, remain elusive. Here, we employed affinity pull‐down and quantitative LC‐MS/MS analyses with FMRP. We identified known and novel candidate FMRP‐binding proteins as well as protein complexes. FMRP interacted with 180 proteins, 28 of which interacted with its N terminus. Interaction with the C terminus of FMRP was observed for 102 proteins, and 48 proteins interacted with both termini. This FMRP interactome comprises known FMRP‐binding proteins, including the ribosomal proteins FXR1P, NUFIP2, Caprin‐1, and numerous novel FMRP candidate interacting proteins that localize to different subcellular compartments, including CARF, LARP1, LEO1, NOG2, G3BP1, NONO, NPM1, SKIP, SND1, SQSTM1, and TRIM28. Our data considerably expand the protein and RNA interaction networks of FMRP, which thereby suggest that, in addition to its known functions, FMRP participates in transcription, RNA metabolism, ribonucleoprotein stress granule formation, translation, DNA damage response, chromatin dynamics, cell cycle regulation, ribosome biogenesis, miRNA biogenesis, and mitochondrial organization. Thus, FMRP seems associated with multiple cellular processes both under normal and cell stress conditions in neuronal as well as non‐neuronal cell types, as exemplified by its role in the formation of stress granules.

Landscape Of M6a RNA Methylation Regulators and Tumor Microenvironment Cell-Infiltration Characterization In Gastroesophageal Adenocarcinomas

“…Barceló et al [34] reported that HNRNPA2B1 acts as a regulator of KRAS-dependent tumorigenesis through the critical pancreatic ductal adenocarcinoma cells signaling pathway PI3K/AKT. FMR1 gene and consequently lack of synthesis of FMR protein (FMRP) is associated with fragile X syndrome, and FMRP plays a critical role in chromatin dynamics, RNA binding, mRNA transport, and mRNA translation [35,36]. Jianhao Li et al [37] indicated that high expression of KIAA1429 and HNRNPA2B1 were signi cantly associated with poor prognosis in osteosarcoma, and m 6 A regulators might be involved in osteosarcoma progression through humoral immune response.…”

The Fragile X Mental Retardation Protein protects the lung from xenobiotic stress by facilitating the Integrated Stress Response

“…The analysis of FMRP-binding proteins in neuronal and other tissues has identified numerous interacting partners. Interestingly, among these interacting partners are the proteins Caprin1 and G3BP that have independently been implicated in the induction of the ISR pathway in response to stress (Taha MS et al, 2020; Wu Y et al, 2016). Pertinently, both Caprin1 and G3BP1 have been shown to be important for eIF2α phosphorylation (Reineke LC et al, 2015).…”

FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

“…The R138Q mutation resides within the extreme C-terminus of this domain and this mutant does not support FMRP-dependent roles in the DNA damage response of cells. Furthermore, the FMRP N-terminus interacts with at least 76 different proteins (46), including CYFIP1/2 and NUFIP1/2 (47)(48)(49). While the cellular role of most of these proteins are still unclear, CYFIP1/2 are key components of the Wave Regulatory Complex required for actin remodelling (50,51).…”