STIMulating IRE1: How store-operated Ca²⁺ entry intersects with ER proteostasis

Area of Science:

• Cellular Biology
• Molecular Biology
• Physiology

Background:

• The endoplasmic reticulum (ER) is crucial for maintaining intracellular calcium (Ca²⁺) homeostasis.
• ER Ca²⁺ depletion triggers store-operated Ca²⁺ entry (SOCE) via STIM1/Orai1 at ER-plasma membrane contact sites (MCSs).
• ER Ca²⁺ depletion also activates the unfolded protein response (UPR) to ensure ER proteostasis.

Discussion:

• This study investigates the interaction between IRE1 and STIM1 within the ER lumen.
• The research highlights a bidirectional regulatory mechanism between IRE1 and STIM1.
• This interaction is shown to control the assembly of ER-plasma membrane contacts.

Key Insights:

• A novel bidirectional control between IRE1 and STIM1 within the ER lumen has been identified.
• This IRE1-STIM1 interplay regulates the formation of ER-plasma membrane contact sites.
• The regulation of MCSs by IRE1 and STIM1 directly impacts store-operated Ca²⁺ entry (SOCE).

Outlook:

• Understanding this crosstalk is vital for comprehending sustained T-cell activation.
• This mechanism is also relevant for processes like myoblast differentiation.
• Further research could explore therapeutic strategies targeting this pathway for immune and muscle disorders.