Acidosis promotes exon skipping through sequestering SR-rich splicing factors in nuclear speckles.

Abstract

Deregulation of alternative splicing has long been associated with aggressive cancer phenotypes characterized by acute or chronic acidosis. Recently, it was hypothesized that this deregulation results from the sequestration of SR-rich splicing factors in nuclear speckles. However, this hypothesis lacked experimental evidence. Here, we demonstrate that, within the pH range consistent with acidosis, phosphorylated SR-rich fragments of splicing factors undergo a phase transition in minimal and multicomponent models of nuclear speckles. This acidification effect resembles the effect of SR dephosphorylation. We explain the molecular basis of this effect and visualize analogous transitions of nuclear speckles in acidified human cells. We also analyze splicing alterations in response to prolonged acidification. The most frequent alteration is exon skipping, consistent with the inaccessibility of SR-rich splicing factors, which normally promote exon inclusion. Our results support the previously proposed hypothesis and deepen the understanding of splicing regulation.