Unconventional splicing of XBP-1 mRNA in the unfolded protein response

Abstract

Cytoplasmic splicing is one of the major regulatory mechanisms of the unfolded protein response (UPR). The molecular mechanism of cytoplasmic splicing is unique and completely different from that of conventional nuclear splicing. The mammalian substrate of cytoplasmic splicing is XBP1 pre-mRNA, which is converted to spliced mRNA in response to UPR, leading to the production of an active transcription factor [pXBP1(S)] responsible for UPR. Interestingly, XBP1 pre-mRNA is also translated into a functional protein [pXBP1(U)] that negatively regulates the UPR. Thus, mammalian cells can quickly adapt to a change in conditions in the endoplasmic reticulum by switching proteins encoded in the mRNA from a negative regulator to an activator. This elaborate system contributes to various cellular functions, including plasma cell differentiation, viral infections, and carcinogenesis. In this short review, I briefly summarize research on cytoplasmic splicing and focus on current hot topics.