Competition between two HUSH complexes orchestrates the immune response to retroelement invasion

Area of Science:

• Epigenetics
• Molecular Biology
• Immunology

Background:

• The human silencing hub (HUSH) complex is crucial for genome integrity via epigenetic repression of invasive elements.
• Loss of specific HUSH subunits (MPP8, Periphilin) triggers interferon signaling, but TASOR loss does not, creating a paradox.

Purpose of the Study:

• To resolve the paradox of HUSH subunit function in genome defense and immune signaling.
• To characterize a novel HUSH complex involving TASOR2 and its role in gene regulation.

Main Methods:

• Characterization of a second HUSH complex involving TASOR2.
• Analysis of HUSH complex assembly and subunit competition.
• Investigation of HUSH roles in repressing retroelements (LINE-1) and interferon-stimulated genes.

Main Results:

• A second HUSH complex, HUSH2, was identified, sharing MPP8 and Periphilin with the canonical HUSH complex but assembling around TASOR2.
• HUSH complexes exhibit subunit competition: retroelement silencing sequesters shared subunits, impacting HUSH2 complex formation and immune gene repression.
• HUSH2, recruited by IRF2, represses interferon-stimulated genes, while the canonical HUSH complex represses LINE-1 retroelements via H3K9me3.

Conclusions:

• Two distinct HUSH complexes with opposing roles in genome defense and immune response were discovered.
• Competition for shared subunits between HUSH complexes links epigenetic silencing of retroelements with immune response regulation.
• This study reveals a novel mechanism coupling epigenetic and immune aspects of genome defense.