Production of BBF2H7‐derived small peptide fragments via endoplasmic reticulum stress‐dependent regulated intramembrane proteolysis

Abstract

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractIntramembrane cleavage of transmembrane proteins is a fundamental cellular process to produce important signals that elicit biological responses. These proteolytic events are known as regulated intramembrane proteolysis (RIP). ATF6 and BBF2H7 are transmembrane basic leucine zipper transcription factors and are subjected to RIP by site-1 protease (S1P) and site-2 protease (S2P) sequentially in response to endoplasmic reticulum (ER) stress. However, the detailed mechanisms responsible for RIP of the transcription factors, including the precise cutting sites, are still unknown. In this study, we demonstrated that S1P cleaves BBF2H7 just before the RXXL S1P recognition motif. Conversely, S2P cut at least three different sites in the membrane (next to Leu380, Met381, and Leu385), indicating that S2P cleaves the substrates at variable sites or via a multistep process. Interestingly, we found BBF2H7-derived small peptide (BSP) fragments located between the S1P and S2P cleavage sites in cells exposed to ER stress. Major type of BSP fragments was composed of 45 amino acid including partial transmembrane and luminal regions and easily aggregates like amyloid β (Aβ) protein. These results advance the understanding of poorly characterized ER stress-dependent RIP. Furthermore, the aggregable peptides produced by ER stress could link to the pathophysiology of neurodegenerative disorders. |MATSUHISA eT Al.

Non-canonical Endoplasmic Reticulum Stress Transducers CREB3 family in cancer and other diseases

“…Like other UPR proteins, in normal physiological conditions, CREB3L2 is unstable and can be degraded by the ubiquitin protease pathway. In the presence of ER stress, on the contrary, the stability of the CREB3L1 protein is increased 10,31 , and subsequently activated, transported from the ER to the Golgi apparatus, where the regulated intramembrane proteolysis (RIP) occurs 32 . Upon cleavage, the N-terminal fragment of CREB3L2 undergoes nuclear translocation and binds to the cyclic AMP-responsive element (CARE) site.…”

“…This BSP peptide tends to aggregate like amyloid β (Aβ) proteins. The production of aggregated peptides may be closely associated with the pathogenesis of neurodegenerative diseases 32 .…”