Nuclear Roles for Canonically Lysosomal Proteases

While the cysteine proteases legumain and cathepsins have traditionally been known as "lysosomal" proteases, there is increasing evidence to suggest that they also contribute to a wide range of extralysosomal processes, including in the nucleus. This review aims to provide a comprehensive overview of the current knowledge regarding the translocation of these proteases to the nucleus and their functions on arrival. We discuss possible mechanisms for transporting these proteases to the nucleus, including the presence of a nuclear localization signal sequence or hitchhiking on other proteins that possess this sequence. This transport requires the proteases to first reach the cytosol, which may occur via direct cytosolic translation of truncated proteases or downstream of lysosomal membrane permeabilization. We also discuss the evidence for functions of these proteases upon arrival to the nucleus, including cell cycle progression, cell differentiation, cell death, immune regulation, and epigenetic regulation. As protease substrate profiling methods continue to improve, it is anticipated that many new nuclear substrates and interacting partners will be identified to reveal additional functions for nuclear proteases.