SUMO operates from a unique long tandem repeat to keep innate immunity in check

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• The SUMO pathway generally suppresses innate immunity in myeloid cells.
• Disrupting sumoylation initiates a potent type I interferon (IFN1) response, escalating inflammation.
• Sumoylation inhibitors have shown potential in preclinical models for activating antitumor immunity.

Purpose of the Study:

• To elucidate the mechanism by which sumoylation represses immune signaling.
• To identify key regulators and pathways involved in sumoylation-mediated immune suppression.

Main Methods:

• Identification of SUMO2/3 substrates in myeloid cells using proteomics.
• Analysis of gene regulation and 3D genome organization upon sumoylation inhibition.
• Investigating the interaction and function of MORC3 and PU.1 in IFNB1 regulation.
• Assessing the role of sumoylation and MORC3 ATPase activity in gene repression.

Main Results:

• MORC3 identified as a key negative regulator of IFNB1 and a major SUMO2/3 substrate.
• Sumoylation represses basal IFNB1 via a MORC3-regulated element (MRE) containing PU.1 motifs.
• Inhibition of sumoylation triggers 3D genome reorganization at the MRE, altering chromatin marks and recruiting PU.1.
• MORC3 is recruited to the MRE but fails to repress IFNB1 upon sumoylation inhibition, highlighting the importance of the SUMOylation and MORC3 ATPase cycle.

Conclusions:

• Uncovered a novel mechanism where sumoylation and MORC3 collaborate to maintain a repressed chromatin state at the IFNB1 locus.
• This process prevents aberrant myeloid-specific immune responses.
• Findings provide insights into targeting the SUMO pathway for immunotherapy.