Cholesterol sensing by the SCAP-FAM134B complex regulates ER-phagy and STING innate immunity.

Area of Science:

• Cell Biology
• Molecular Biology
• Immunology

Background:

• The endoplasmic reticulum (ER) plays a critical role in cholesterol homeostasis.
• ER cholesterol levels influence cellular signaling pathways.
• The precise mechanisms linking ER cholesterol to signaling remain largely unknown.

Purpose of the Study:

• To elucidate the role of ER cholesterol in cellular signaling.
• To identify proteins involved in sensing ER cholesterol levels.
• To understand the regulation of ER-phagy and immune responses by cholesterol.

Main Methods:

• Co-immunoprecipitation assays to study protein interactions.
• Cholesterol level measurements in the ER.
• Analysis of ER-phagy and STING activation.
• SREBP2 activation assays.

Main Results:

• FAM134B directly interacts with cholesterol and SCAP.
• High ER cholesterol promotes FAM134B-SCAP complex formation, inhibiting ER-phagy, STING activation, and cholesterol synthesis.
• Low ER cholesterol leads to FAM134B dissociation from SCAP, activating SREBP2 for cholesterol synthesis and promoting ER-phagy and STING-mediated immune responses.

Conclusions:

• The SCAP-FAM134B complex acts as a sensor for ER cholesterol levels.
• This complex integrates cholesterol sensing with the regulation of ER-phagy and innate immune signaling.
• Dysregulation of this pathway has implications for cholesterol-related diseases.