DHHC21 is a STIM1 protein S-acyltransferase that modulates immune function in vivo

Area of Science:

• Cellular Biology
• Biochemistry
• Immunology

Background:

• Store-operated calcium entry (SOCE) regulates cellular calcium levels.
• STIM1 and STIM2 proteins sense ER calcium depletion and activate Orai channels.
• Dynamic S-acylation of Orai1 and STIM1 is essential for SOCE.

Purpose of the Study:

• To investigate the role of DHHC21 in SOCE.
• To determine if DHHC21 activation is required for STIM1 S-acylation and calcium entry.
• To explore the physiological relevance of DHHC21 in vivo and its connection to autoimmune lymphoproliferative syndrome (ALPS).

Main Methods:

• In vitro and in vivo studies using wild-type and 'depilated' mouse models.
• Analysis of STIM1 S-acylation and calcium channel activity.
• Assessment of ALPS-related phenotypes in 'depilated' mice.

Main Results:

• DHHC21 is essential for SOCE in vitro and in vivo.
• DHHC21 activation is required for STIM1 S-acylation and calcium entry.
• DHHC21 dynamically localizes to Orai1/STIM1 puncta and binds STIM1.
• 'Depilated' mice exhibit ALPS-like symptoms, including defective T cell death and neutropenia.

Conclusions:

• Dynamic S-acylation mediated by DHHC21 is critical for SOCE and immune function.
• DHHC21 plays a significant role in regulating calcium signaling pathways.
• Targeting DHHC21 could be a therapeutic strategy for ALPS and related disorders.