This week, we explore a fascinating protein that regulates the unfolded protein response (UPR) in eukaryotic cells in an unusual manner - by sensing the accumulation of unfolded proteins in the endoplasmic reticulum (ER) lumen and conveying this information to the nucleus. This is achieved through unconventional splicing of the XBP1 mRNA in the cytoplasm leading to the induction of a transcriptional program in the nucleus. Hence its apt name - Endoplasmic Reticulum to Nucleus Signaling, ERN1.

Throughout our daily lives, our cells are exposed to various stressors. Environmental factors such as starvation, hypoxia, viral infections, and heat can cause proteins in the ER to lose their proper structure and unfold (Malhotra and Kaufman 2007; Schroder and Kaufman, 2005). The accumulation of these misfolded proteins becomes an alarming situation for the cell called ER stress. To alleviate this stress, the ER must communicate the information to the nucleus, prompting a response that restores cellular homeostasis. In this intricate and evolutionary conserved system, ERN1 plays a central role.

ERN1 was first discovered in Saccharomyces cerevisiae in 1993 (Cox, 1993), with its mammalian homolog identified in 1998 (Tirasophon, 1998). It was discovered as a transmembrane protein distributed throughout the ER membrane. On the ER lumen side, it features a serine/threonine kinase domain that senses the accumulation of accumulated unfolded proteins, mediated by the dissociation of the chaperone BiP, from ERN1´s lumenal domain (Bertolotti, 2000). This interaction causes ERN1 to homooligomerize within the ER membrane, triggering trans-autophosphorylation (Zhou, 2006 ; Korennykh, 2009). This activation leads to the initiation of its endoribonuclease activity on the cytoplasmic side, which specifically targets a single mRNA species - the bZIP transcription factor XBP1 (Yoshida, 2001). The last leg of the pathway involves the ERN1 splicing of the XBP1 mRNA, enabling it to be translated into an active transcription factor protein. Once in the nucleus, XBP1 will initiate a transcriptional program that produces proteins essential for restoring ER homeostasis ( Lee 2003 ; Acosta-Alvear 2007).

In summary, ERN1 is a key sensor in the unfolded protein response, detecting ER stress and activating transcriptional programs that restore balance in the cell. Its highly conserved role in splicing XBP1 mRNA makes it a critical regulator of cellular stress responses, highlighting its biological importance in maintaining protein homeostasis across diverse organisms.