Reactome | Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex

Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex

Stable Identifier

R-HSA-9843970

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex

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The Human Silencing Hub (HUSH) complex comprises MPHOSPH8 (MPP8), Periphilin (PHPLN1), and TASOR, which appears to act as a scaffold that binds the other subunits (reviewed in Seczynska and Lehner 2023). The HUSH complex preferentially represses transcription of young LINE1 retroelements (Liu et al. 2018, Robbez-Masson et al. 2018) and some HIV integrants (Tchasovnikarova et al. 2015, Zhu et al. 2018, Chougui and Margottin-Goguet 2019).
The HUSH complex creates repressive chromatin in two ways (reviewed in Seczynska and Lehner 2023). Firstly, HUSH can cause spreading of existing heterochromatin by binding existing trimethylated H3K9 and recruiting SETDB1 to trimethylate H3K9 of adjacent nucleosomes (Tchasovnikarova et al. 2015). Secondly, HUSH can initiate heterochromatin by binding nascent transcripts via its PHPLN1 subunit and recruiting SETDB1 to trimethylate lysine-9 of histone H3 (H3K9) at the locus being transcribed (Seczynska et al. 2022).
By an uncharacterized mechanism, the HUSH complex targets long intronless cDNAs, such as those produced by retroelements, as well as unusually long exons of normal cellular genes (Seczynska et al. 2022). Introns somehow protect against silencing by HUSH, though actual splicing is not required (Seczynska et al. 2022). In mice, ZNF638 (NP220, Znf638 gene) recruits the HUSH complex to unintegrated murine leukemia virus (MLV) (Zhu et al. 2018) and in human cells ZNF638 (NP220) and HUSH silence recombinant adeno-associated viruses (Das et al. 2022). The potential recruitment of HUSH by ZNF638 to human retroelements is not yet demonstrated.

Literature References

PubMed ID	Title	Journal	Year
30487602	NP220 mediates silencing of unintegrated retroviral DNA Goff, SP, Wang, GZ, Zhu, Y, Cingöz, O	Nature	2018
29211708	Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators Gu, B, Swigut, T, Bassik, MC, Grow, E, Liu, N, Lee, CH, Wysocka, J	Nature	2018
36754727	The sound of silence: mechanisms and implications of HUSH complex function Seczynska, M, Lehner, PJ	Trends Genet	2023
29728366	The HUSH complex cooperates with TRIM28 to repress young retrotransposons and new genes Robbez-Masson, L, Rowe, HM, Conde, L, Timms, RT, Tchasovnikarova, IA, Herrero, J, Tunbak, H, Tie, CHC, Lehner, PJ, Husovsky, C	Genome Res	2018
34878926	Epigenetic Silencing of Recombinant Adeno-associated Virus Genomes by NP220 and the HUSH Complex Das, A, Walton, EM, Stafford, VG, Asokan, A, Fiflis, DN, Vijayan, M	J Virol	2022
34794168	Genome surveillance by HUSH-mediated silencing of intronless mobile elements Cuesta, SM, Seczynska, M, Bloor, S, Lehner, PJ	Nature	2022
30809215	HUSH, a Link Between Intrinsic Immunity and HIV Latency Margottin-Goguet, F, Chougui, G	Front Microbiol	2019
26022416	GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells Dougan, G, Timms, RT, Tchasovnikarova, IA, Göttgens, B, Matheson, NJ, Wals, K, Lehner, PJ, Dawson, MA, Antrobus, R	Science	2015