N-terminal truncation diversifies USP18 function during early myogenesis

Ubiquitin-specific protease 18, commonly known as USP18, is a protein predominantly investigated for its involvement in type-I interferon (IFN-I) signaling pathways. However, USP18 also plays a role in the development of muscle cells, a function that does not rely on IFN-I signaling. USP18 exists in two forms: a common long isoform (LF) and a shorter isoform (SF), produced through N-terminal truncation.

The SF form accumulates in the nucleus during the process of muscle differentiation, although the specific functions of this SF form are not well understood.

In a study comparing the USP18 SF and LF forms in muscle cells, researchers found that these forms have distinct features related to their N-termini. These differences are linked to variations in protein stability, localization within the cell, and interactions with other proteins. The SF form shows a significantly larger network of protein interactions, particularly with nuclear proteins, chaperones, and proteins involved in maintaining protein homeostasis.

Functionally, the SF form of USP18 promotes an early stage of muscle cell development and is linked to alterations in the splicing of certain genes, including those crucial for forming sarcomeres, the functional units of muscle tissue. These findings suggest that the USP18 protein can adopt diverse roles depending on its isoform, with the SF form acting as a possible regulator of muscle differentiation.

The study emphasizes that the N-terminus of USP18 is a key factor in determining its non-standard functions and the variety of proteoforms it can produce.