Endoplasmic reticulum membrane reorganization is regulated by ionic homeostasis

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• A novel, evolutionarily conserved cellular stress response involving endoplasmic reticulum (ER) membrane reorganization has been identified.
• This response is distinct from canonical ER stress and the unfolded protein response (UPR).
• Apogossypol, a BCL-2 family antagonist, was initially used to induce this ER membrane reorganization.

Purpose of the Study:

• To identify common mechanisms underlying ER membrane reorganization induced by structurally diverse chemicals.
• To investigate the role of ion homeostasis in this novel cellular stress response.

Main Methods:

• Microarray analysis and connectivity mapping to identify chemicals inducing ER membrane reorganization.
• Hierarchical clustering of transcription profiles for chemicals causing membrane reorganization.
• Experimental validation using agents affecting Ca(2+) homeostasis (thapsigargin, calmodulin antagonists) and STIM1 overexpression.

Main Results:

• Hierarchical clustering revealed two distinct clusters of chemicals inducing ER membrane reorganization, one linked to Ca(2+) homeostasis.
• ER membrane reorganization was induced by agents that deplete ER Ca(2+) or alter cellular Ca(2+) handling.
• Extracellular Na(+) influx, but not Ca(2+) influx, was required for ER membrane reorganization induced by apogossypol and TW37.

Conclusions:

• Perturbation of ionic homeostasis, including both Ca(2+) and Na(+) balance, is a key mechanism regulating ER membrane reorganization.
• This novel, non-canonical ER stress response and its mechanisms are evolutionarily conserved.
• The findings highlight a new cellular stress pathway with implications for understanding cellular responses to chemical insults.