Abstract：
The human silencing hub (HUSH) preserves genome integrity through the epigenetic repression of invasive genetic elements. However, despite our understanding of HUSH as an obligate complex of three subunits, only loss of MPP8 or Periphilin, but not TASOR, triggers interferon signaling following derepression of endogenous retroelements. Here, we resolve this paradox by characterizing a second HUSH complex that shares MPP8 and Periphilin but assembles around TASOR2, an uncharacterized paralog of TASOR. Whereas HUSH represses LINE-1 retroelements marked by the repressive histone modification H3K9me3, HUSH2 is recruited by the transcription factor IRF2 to repress interferon-stimulated genes. Mechanistically, HUSH-mediated retroelement silencing sequesters the limited pool of the shared subunits MPP8 and Periphilin, preventing TASOR2 from forming HUSH2 complexes and hence relieving the HUSH2-mediated repression of interferon-stimulated genes. Thus, competition between two HUSH complexes intertwines retroelement silencing with the induction of an immune response, coupling epigenetic and immune aspects of genome defense.
摘要：
人类沉默中心（HUSH）通过入侵遗传元件的表观遗传抑制保持基因组完整性。然而,尽管我们认为HUSH是一个由三个亚基组成的专属性复合体,仅丢失MPP8或Periphilin，但不是TASOR,内源性反转录因子抑制后引发干扰素信号传导。这里,我们通过表征第二个HUSH复合物来解决这一悖论，该复合物共享MPP8和Periphilin，但围绕TASOR2组装，TASOR2是一种未表征的TASOR类似物。尽管HUSH抑制以抑制性组蛋白修饰H3K9me3标记的LINE-1逆转录元件，但HUSH2被转录因子IRF2招募以抑制干扰素刺激的基因。机械上,HUSH介导的逆转录元件沉默隔离了共享亚基MPP8和Periphilin的有限池，防止TASOR2形成HUSH2复合物，从而缓解HUSH2介导的干扰素刺激基因抑制。因此，两个HUSH复合物之间的竞争交织逆转录元件沉默诱导免疫应答，基因组防御的表观遗传和免疫方面的耦合。
