Fazili, K. M. | bioRxiv Science

bioRxiv2021

sMEK1 promotes crosstalk between IRE1 and Akt signaling pathway: Evidence for a novel IRE1/sMEK1/Akt complex

The Unfolded Protein Response (UPR) is a dynamic cellular pathway that helps maintain proteostasis during endoplasmic reticulum (ER) stress. One of the key UPR sensors is IRE1, which plays a central role in managing ER stress and interacts with other cellular pathways to regulate cell homeostasis. The Akt signalling pathway, on the other hand, is a crucial survival pathway involved in diverse cellular functions like growth, proliferation, glucose metabolism, and survival. This study explores the interplay between these two important cell signalling pathways. Specifically, our study revealed that IRE1 negatively regulates Akt through the protein phosphatase sMEK1. We identified sMEK1 and Akt as novel interacting partners of IRE1, which together form a ternary complex that helps coordinate the IRE1 and Akt signalling networks. The IRE1/sMEK1/Akt ternary complex results in the dephosphorylation of Akt by sMEK1 in the presence of activated IRE1. Together, this study sheds light on the molecular mechanism underlying the UPR/Akt link and provides valuable insights into the overall impact of their interaction.

cell biology↗

bioRxiv2019

Bid as a novel interacting partner of IRE1 differentially regulating its RNAse activity

Unfolded protein response is a dynamic signalling pathway, which is involved in the maintenance of proteostasis and cellular homeostasis. IRE1, a transmembrane signalling protein represents the start point of a highly conserved UPR signalling cascade. IRE1 is endowed with kinase and endoribonuclease activities. The activation of the kinase domain of IRE1 by trans-autophosphorylation leads to the activation of its RNAse domain. RNAse domain performs atypical splicing of Xbp1 mRNA and degradation of mRNAs by an effector function known as Regulated IRE1 Dependent Decay (RIDD). The regulation of the distinctive nature of the IRE1 ribonuclease function is potentially mediated by a dynamic protein structure UPRosome that is an assembly of a huge number of proteins on IRE1. Here, we reported that Bid is a novel recruit to UPRosome, which directly interacts with the cytoplasmic domain of IRE1. Bid controls the auto-phosphorylation of IRE1 in a negative manner where Bid overexpression conditions displayed reduced phosphorylation levels of IRE1 and Bid knockdown cells showed slightly enhanced IRE1 phosphorylation. This effect was reciprocated with JNK, a downstream target of IRE1. Our Insilico analysis revealed that Bid binding to IRE1 dimer averts its structural flexibility and thereby preventing its trans-autophosphorylation activity. We found that the effect of Bid is specific to the IRE1 branch of UPR signalling and competitive in nature. The highlighting observation of the study was that Bid stimulated a differential activity of the IRE1 RNAse domain towards Xbp1 splicing and RIDD. These results together establish that Bid is a part of the UPRosome and modulates IRE1 in a way to differentially regulate its RNAse outputs.

cell biology↗