hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation

Abstract

Highlights d hnRNPDL requires both N-and C-terminal IDRs to phase separate d The absence of N-terminal IDR facilitates aggregation d The unique combination of IDRs in each isoform determines its cellular behavior d D378N/H mutations accelerate hnRNPDL aggregation and compromise its solubility

Relevance of Electrostatic Charges in Compactness, Aggregation, and Phase Separation of Intrinsically Disordered Proteins

“…Instead, the amyloidogenic pathway seems driven by hydrophobic interactions [154]. In line with the behavior of tau, in the case of hnRNPDL, LLPS exerts a protective role against fibril formation [144]. On the contrary, when LLPS is triggered in vitro under high-salt concentrations, thereby becoming partially driven by hydrophobic contacts, a direct correlation with increased amyloid propensity is observed, suggesting that this two phenomena not only could occur under coinciding conditions but could also positively influence one another [154].…”

Phase Separation as a Missing Mechanism for Interpretation of Disease Mutations

“…Different alternative splice isoforms that incorporate or remove different multivalent elements in IDRs (Box 1) have been shown to produce different phase separation propensities and changes in function, with effects mimicking those for insertion and deletion mutations. For example, different protein isoforms can disrupt or modulate phase separation (Smith et al, 2020) or cause irreversible protein aggregation in disease (Batlle et al, 2020). Moreover, changing the multivalent patterns in IDRs may lead to gain-of-toxic function by introducing new interaction partners and activating aberrant pathways (Han et al, 2020).…”

“…Note that HNRNPA2B1 is overexpressed in breast cancers (Hu et al, 2017). Splicing of alternative exons overlapping glycine-tyrosine rich (GY) motifs within hnRNPA/D C-terminal IDRs can regulate their phase separation propensity and splicing functions (Batlle et al, 2020;Gueroussov et al, 2017). Fibrillization can be enhanced in liquid condensed phases (Murakami et al, 2015;Patel et al, 2015), and missense mutations in the IDR of hnRNPA1 leading to pathological fibrillization have been reported (Molliex et al, 2015).…”

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

“…Recently, Bengoechea and collaborators reported an accumulation and co-localization of hnRNPA1 and hnRN-PA2/B1 with DNAJB6 in sarcoplasmic stress granules [67]. Further strengthening the link between hnRNPs and LGMD, hnRNPDL mutations were observed in LGMD1G [153], and are thought to cause disease through aggregation in muscle and loss of function [154].…”