A new study of the IEM CAS describes the mechanism of binding of exoribonuclease Xrn1 to the plasma membrane

Scientists from the Department of Functional Organisation of Biomembranes recently published a new study focusing on a previously little-known way of regulating one of the key factors responsible for mRNA degradation in eukaryotic cells, the exoribonuclease Xrn1. Some time ago, the team showed that the activity of the Xrn1 enzyme is suppressed upon its binding to the eisosome, a protein complex that stabilises a specialised microdomain of the yeast plasma membrane. The new study sought to answer the questions of what the primary stimulus for Xrn1 translocation to the membrane is, and whether the described regulation of Xrn1 activity is restricted to the yeast variant of the enzyme.

The binding of Xrn1 to the eisosome occurs after the yeast has consumed all fermentable sugars from the culture medium. Binding is fully reversible – the enzyme is quickly released back into the cytoplasm and reactivated once the sugars reappear. The temporary inactivation of exoribonuclease at the plasma membrane has two significant advantages. First, it prevents unwanted mRNA degradation under conditions where the cell is forced to conserve energy and obtain it by aerobic metabolism (respiration). The rapid mobilisation of inactivated Xrn1 upon finding new sugar sources, in turn, allows rapid reprogramming of the cellular metabolism back to an anaerobic mode that draws energy from glucose breakdown.

Using fluorescence microscopy, the researchers showed that it is not the mere presence of fermentable sugar in the medium or its successful transport into the cell but only the advanced steps of its downstream processing (glycolysis) that trigger the release of Xrn1 from its plasma membrane binding. They further determined which part of the Xrn1 molecule is necessary for this binding. In addition, by analysing the behaviour of the human Xrn1 variant in yeast cells, they found that the human enzyme follows the same regulatory mechanism as its yeast counterpart.

The study’s results predict a likely mode of regulation of Xrn1 activity when human cells adapt to altered metabolic needs (e.g., during glucose restriction or cancer). Thus, they may have potential implications for clinical practice, particularly in treating metabolic disorders or cancer.

The study was published in the journal Heliyon – Cell Press (open in a new window).