Activation of endoplasmic reticulum stress via clustering of inner nuclear membrane proteins

BioRxiv : the Preprint Server for Biology
S. VidakTom Misteli

Abstract

One of the major cellular mechanisms to ensure protein homeostasis is the endoplasmic reticulum (ER) stress response. This pathway is typically triggered by accumulation of misfolded proteins in the ER lumen. Here we describe activation of ER stress via protein aggregation in the cell nucleus. We find in the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) activation of ER stress due to the aggregation of the diseases-causing progerin protein at the nuclear envelope. The presence of nucleoplasmic protein aggregates is sensed and signaled to the ER lumen via immobilization and clustering of the inner nuclear membrane protein SUN2, leading to activation of the Unfolded Protein Response (UPR). These results identify a nuclear trigger of ER stress and they provide insight into the molecular disease mechanisms of HGPS.

Methods Mentioned

BETA
fluorescence-activated cell sorting
transfection
Illumination Microscopy
confocal microscopy
FCS
PCR
Chip
super-resolution microscopy
transgenic

Software Mentioned

FACSDiva
ZEN
ImageJ
SIM
Huygens Professional
Columbus
Zeiss Zen
Adobe Photoshop
R
Excel

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