OASIS/CREB3L1 is a factor that responds to nuclear envelope stress

Yasunao Kamikawa,Yasunori Horikoshi,Satoshi Tashiro,Masayuki Kaneko,Atsushi Saito,Kazunori Imaizumi,Rie Asada,Koji Matsuhisa

doi:10.1038/s41420-021-00540-x

Yasunao Kamikawa, Yasunori Horikoshi + Show 6 more

Open Access

https://doi.org/10.1038/s41420-021-00540-x

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Abstract

The nuclear envelope (NE) safeguards the genome and is pivotal for regulating genome activity as the structural scaffold of higher-order chromatin organization. NE had been thought as the stable during the interphase of cell cycle. However, recent studies have revealed that the NE can be damaged by various stresses such as mechanical stress and cellular senescence. These types of stresses are called NE stress. It has been proposed that NE stress is closely related to cellular dysfunctions such as genome instability and cell death. Here, we found that an endoplasmic reticulum (ER)-resident transmembrane transcription factor, OASIS, accumulates at damaged NE. Notably, the major components of nuclear lamina, Lamin proteins were depleted at the NE where OASIS accumulates. We previously demonstrated that OASIS is cleaved at the membrane domain in response to ER stress. In contrast, OASIS accumulates as the full-length form to damaged NE in response to NE stress. The accumulation to damaged NE is specific for OASIS among OASIS family members. Intriguingly, OASIS colocalizes with the components of linker of nucleoskeleton and cytoskeleton complexes, SUN2 and Nesprin-2 at the damaged NE. OASIS partially colocalizes with BAF, LEM domain proteins, and a component of ESCRT III, which are involved in the repair of ruptured NE. Furthermore, OASIS suppresses DNA damage induced by NE stress and restores nuclear deformation under NE stress conditions. Our findings reveal a novel NE stress response pathway mediated by OASIS.

Highlights

It had been thought that the nuclear envelope (NE) is stable during interphase [1]
These results indicate that a certain amount of OASIS localizes to the NE, where it might play an important role
Flag-OASIS revealed focal accumulation at those regions where Lamin A/C were absent (Fig. 1F). These results indicate that OASIS accumulates on the damaged NE where the nuclear lamina is disrupted in shRNA against Lamin B1 (shLMNB1) cells

Summary

Introduction

Accumulating evidence has revealed that NE can be damaged by a variety of cellular stresses called “NE stress”, which lead to the degeneration of NE proteins and disruption of their functional interactions [2,3,4,5,6]. NE stress further induces genome instability and cell death [3, 5, 6, 9, 10]. These findings suggest that NE stress perturbs cellular homeostasis and plays crucial roles in the pathogenesis of some diseases caused by dysfunction of NE. Elevated NE stress has been observed in the cells derived from the patients of Hutchinson Gilford Progeria Syndrome (HGPS), which is caused by the mutation in the gene encoding Lamin A [3]

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