Vandermoere, F. | bioRxiv Science

bioRxiv2026

A large-scale analysis of the R2TP chaperone network reveals its contribution to the assembly of INO80, SRCAP and TIP60

HSP90/R2TP is an essential quaternary chaperone composed of RPAP3, PIH1D1 and the RUVBL1/RUVBL2 AAA+ ATPases. These enzymes are also part of the INO80, SRCAP and TIP60 complexes, but the relationship between these chromatin remodelers and R2TP remains unclear. Here, we performed systematic analyses of the R2TP-specific subunits RPAP3 and PIH1D1. We validated 115 interaction partners and found that many were sensitive to HSP90 or R2TP inhibition. In yeast, epistatic screens revealed functional interactions with Ino80, Swr1 (SRCAP) and NuA4 (TIP60). Consistently, human RPAP3 physically interacted with subunits of INO80, SRCAP and TIP60 and was required for the formation of these complexes. More specifically, RPAP3 enabled the co-translational association of RUVBL1/RUVBL2 with the motor subunit of these chromatin remodelers. In vitro, the client-binding domain of RUVBL1/RUVBL2 modulated their interaction with RPAP3, suggesting that client subunits displace RPAP3 from nascent complexes. Thus, R2TP is an early chaperone of TIP60, SRCAP and INO80, which leaves RUVBL1/RUVBL2 as resident scaffolding subunits.

molecular biology↗

bioRxiv2024

Chronic potentiation of metabotropic glutamate receptor 2 with a nanobody accelerates amyloidogenesis in Alzheimer's disease.

Immunotherapy of Alzheimers disease (AD) is a promising approach to reduce the accumulation of amyloid-beta (A{beta}), a critical event in the onset of the disease. Targeting the group II metabotropic glutamate receptors, mGlu2 and mGlu3, could be important in controlling A{beta} production, although their respective contribution remains unclear due to the lack of selective tools. Here, we show that enhancing mGlu2 receptor activity increases A{beta}1-42 peptide production whereas activation of mGlu3 has no effect. We show that such a difference likely results from the direct interaction of APP with mGlu3, but not with mGlu2 receptors, that prevents APP amyloidogenic cleavage and A{beta}1-42 peptides production. We then show that chronic treatments of the AD model 5xFAD mice with a brain-penetrating mGlu2-potentiating nanobody accelerated amyloid aggregation and exacerbated memory deficits, but had no effect in control mice. Our results confirm that a selective mGluR2 activation exacerbates AD disease development, suggesting that therapeutic benefices could be obtained with blockers of this receptor. Our study also provides the proof-of-concept that chronic administration of nanobodies targeting neuroreceptors can be envisioned to treat brain diseases.

neuroscience↗