Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction

Area of Science:

• Cell Biology
• Biophysics
• Molecular Biology

Background:

• Cytosolic phospholipase A2 (cPLA2) releases arachidonic acid from the inner nuclear membrane (INM), a key step in producing inflammatory lipids.
• Calcium ions (Ca2+) and INM tension (TINM) are hypothesized regulators of cPLA2 at the INM.
• The role of endoplasmic reticulum (ER) membrane flow in buffering TINM and its impact on mechanotransduction remains unclear.

Purpose of the Study:

• To investigate whether the ER buffers TINM and to elucidate the conditions governing nuclear membrane mechanotransduction.
• To develop a novel biosensor for measuring INM tension independently of Ca2+.

Main Methods:

• Development of the Ca2+-insensitive INM tension biosensor, ALPIN (amphipathic lipid-packing domain inside the nucleus).
• Confocal time-lapse imaging of ALPIN and cPLA2 interactions with the INM.
• Simultaneous monitoring of ER morphology, nuclear shape/volume, and cell lysis.
• Combining ALPIN imaging with Ca2+-induced ER disruption to establish causality.

Main Results:

• A correlation was observed between TINM and disrupted ER-nuclear membrane contiguity in stressed mammalian cells and in vivo zebrafish models.
• Compensatory membrane flow from the ER buffers TINM but does not prevent it.
• ER disruption during cell stress and death acts as a trigger for nuclear membrane mechanotransduction.

Conclusions:

• The study consolidates the biomechanical basis for cPLA2 activation by nuclear deformation.
• ER membrane dynamics play a crucial role in regulating nuclear membrane tension.
• ER disruption is identified as a novel trigger for nuclear membrane mechanotransduction, impacting inflammatory pathways.