Engineered nuclear import receptor karyopherin-B2 chaperones aberrant phase transitions of disease-associated cargo

Abstract

Karyopherin-β2 (Kapβ2) is a nuclear import receptor (NIR) that localizes proteins bearing a proline-tyrosine nuclear localization signal (PY-NLS) to the nucleus, including the RNA-binding protein (RBP) FUS. Recent work has demonstrated that NIRs can chaperone RBPs in vitro and in cells, preventing and reversing their self-assembly and aggregation. However, when the PY-NLS is mutated, Kapβ2 no longer efficiently chaperones its cargo. Here, we focus on the case of FUSP525L, an RBP NLS mutant associated with a highly aggressive form of juvenile ALS.