【PNAS】The research group of Ma Xianjue/Li Xu of Westlake University revealed a new mechanism of UPR regulation of Hippo signaling pathway mediated tumor progression

This article is the original of Translational Medicine Network, please indicate the source of reprinting

By Jevin

The unfolded protein response (UPR) is thought to coordinate cell growth and proliferation by controlling endoplasmic reticulum (ER) protein balance, however, the mechanism behind this process is unclear
.
Therefore, by using fruit flies, mammalian models, and human databases, the researchers discovered the dual role
of Ire1/Xbp1s in development and tumorigenesis.

On October 10, 2022, Ma Xianjue's research group at the School of Life Sciences, Westlake University and Li Xu's research group jointly published a research paper elaborating the molecular mechanism
of the Ire1/Xbp1s branch of UPR regulating organ size, intestinal stem cell homeostasis, cell migration and tumorigenesis and development through the Hippo pathway.
At the same time, it is revealed that the interaction between Bip and Yorkie/YAP determines that Ire1/Xbp1s have dual functions
in the growth and invasion of primary tumors.
The study was published in Proceedings of the National Academy of Sciences
.

style="box-sizing: border-box;" _msthash="251139" _msttexthash="2181517">The mechanism of intratumoral activation of UPR is unknown

 01 

The growth and proliferation of cells during development depend on a large amount of protein synthesis, and misfolding proteins
will inevitably occur due to random errors in protein translation, folding failures, etc.
during this high-intensity processing.
As a factory for protein processing, the endoplasmic reticulum relieves the pressure of protein synthesis and folding to coordinate rapid cell division and proliferation, thereby maintaining homeostasis
.

When the endoplasmic reticulum pressure exceeds a certain threshold and the activation of UPR fails to relieve the endoplasmic reticulum pressure, apoptosis
will be triggered.
Cancer cells also require a large amount of protein synthesis during malignant proliferation, so studies have shown that UPR is also activated in tumors, but the mechanism behind this process is unclear
.

Drosophila, a mammalian model

 02

In this study, the researchers first modeled different types of malignancy in Drosophila and found that UPR was significantly activated
.
UPR activation re-establishes endoplasmic reticulum homeostasis by initiating a series of signal transduction pathways from the endoplasmic reticulum to the nucleus
by initiating a series of signal transduction pathways from the endoplasmic reticulum to the nucleus.
In order to explore the role of various branches of UPR in tumorigenesis and development, the researchers used gene overexpression and RNA interference techniques to find that overexpression Ire1/Xbp1s specifically activated the Hippo signaling pathway to inhibit tumor growth
.

Through genetic analysis, the researchers also found that Yorkie, the effector downstream of the hippo signaling pathway, is necessary
in Ire1/Xbp1 to regulate organ size.
In the following work, the authors further discovered that Bip, as a downstream key regulator of Xbp1s, can regulate organ size and inhibit tumor growth
by interacting with Yorkie to anchor it in the cytoplasm and restrict its entry into the nucleus.
In addition, they found that there is a negative feedback counterbalance mechanism
for UPR signals to regulate the Hippo signaling pathway.

The dual role of IRE1