Staufen2 isoforms localize to the somatodendritic domain of neurons and interact with different organelles

Abstract

Mammalian Staufen2 (Stau2) is involved in mRNA transport in neurons. Here,we report that Stau2 is a double-stranded RNA-binding protein that is mainly expressed in the brain. We show that Stau2 is found in the somatodendritic compartment of neurons. In dendrites, Stau2 is aligned on individual tracts and colocalizes with microtubules. Stau2 is expressed as at least three splice isoforms, which can be observed in several subcellular complexes. Although a 62 kDa isoform (Stau262) fractionates in ribosome-free fractions of light density, Stau259 and Stau252 are found in high-density complexes. These complexes are resistant to EDTA and to non-ionic detergent. For the first time, we also provide evidence for an interaction of some Stau2 isoforms with ribosomes, thus pointing to an interesting new role for Stau2 in translation. EDTA treatment, which dissociates ribosome subunits,does not release Stau2 from the subunits, suggesting that Stau2-ribosome associations are not mediated mainly by mRNA intermediates. Although Stau2 has many features in common with its paralogue Stau1, it does not colocalize with Stau1-containing particles, indicating that these proteins are components of different complexes in dendrites. Our findings suggest that members of the Staufen family share evolutionarily conserved properties and highlight the complexity of Staufen-mediated RNA transport in neurons.

Staufen blocks autophagy in neurodegeneration

“…STAU1 and STAU2 are a dsRBP. They are found in stress granules (SGs) in brain oligodendrocytes and neurons and modulate SG dynamics 13,[41][42][43] . Owing to Staufen's ability to function as an RBP, it is involved in regulating RNA metabolism, mRNA transport in neuronal dendrites, and other cells in vertebrates [44][45][46] .…”

Staufen from embryo polarity to cellular stress and neurodegeneration

“…Besides being an RNA granule-forming protein by means of RNA-protein and protein-protein interactions (21,31,32) Staufen associates to and regulates the translational apparatus (33)(34)(35). We and others have demonstrated that Staufen 1 and 2 associates to polysomes located at myelin processes and at post-synaptic densities (33,34), and to polysomes and ribosomal subunits in primary neurons and fibroblast cells lines, all this supporting a regulatory role in translation (11,16,31,35). More recently, we have found that Staufen is a conserved component of SGs, which are granular accretions of RNPs specifically assembled in a transient manner during the cellular response to stress.…”

“…In recent years, a number of research groups have focused on this highly conserved protein and its role on the regulation of cytoplasmic post-transcriptional processes in mammalian CNS cells (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Two paralog genes are present in vertebrates, Staufen 1 and Staufen 2, and both proteins have been implicated in mRNA localization.…”

The Staufen1‐dependent cell cycle regulon or how a misregulated RNA‐binding protein leads to cancer

“…This study reveals that STAU1 can take three different conformations in solution, that it is a highly flexible protein and highlights the importance of neighbouring double‐stranded RNA‐binding domains (dsRBDs) for substrate specificity. STAU1 binds RNA through two dsRBDs (dsRBD3 and 4) which both adopt a canonical α–β–β–β–α dsRBD fold (Wickham et al ., 1999; Ramos et al ., 2000; Duchaine et al ., 2002; Martel et al ., 2010; Gleghorn et al ., 2013; Gleghorn & Maquat, 2014; Lazzaretti et al ., 2018; Visentin et al ., 2020; Yadav et al ., 2020). It is proposed that the flexible dsRBD3/4 tandem recognizes RNA in a multistep process: dsRBD3 recognizes and scans dsRNAs, allowing the recruitment of dsRBD4 on the SBS.…”

“…Two Staufen paralog genes, STAU1 and STAU2 , are expressed from different loci in vertebrates (Buchner et al ., 1999; Brizard, Luo & DesGroseillers, 2000). Although STAU1 and STAU2 proteins are sometimes found as heterodimeric complexes (Park, Gleghorn & Maquat, 2013), they mostly form independent ribonucleoprotein complexes (RNPs) and regulate different physiological pathways (Duchaine et al ., 2002; Furic, Maher‐Laporte & DesGroseillers, 2008; Lebeau et al ., 2008, 2011; Hassine et al ., 2020). In this review, we focus on STAU1 and review recent evidence linking STAU1 to post‐transcriptional regulation of gene expression and to cancer.…”