This family contains periphilin (PPHLN1), a component of the Human Silencing Hub (HUSH) complex containing three proteins: periphilin, TASOR and MPP8 (also called MPHOSPH8) and mediates epigenetic repression. The HUSH complex is recruited to genomic loci rich in H3K9me3 and is required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3 (histone H3 lysine 9 trimethylation), as well as MORC2, a DNA-binding ATPase. The HUSH complex is also involved in the silencing of unintegrated retroviral DNA by being recruited by ZNF638: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed. In human, periphilin-1, the protein encoded by the gene PPHLN1, is involved in epithelial differentiation and contributes to epidermal integrity and barrier formation. It is one of the several proteins that become sequentially incorporated into the cornified cell envelope during the terminal differentiation of keratinocyte at the outer layers of epidermis. This protein interacts with periplakin, which is known as a precursor of the cornified cell envelope. The cellular localization pattern and insolubility of this protein suggest that it may play a role in epithelial differentiation and contribute to epidermal integrity and barrier formation. Oncogenic fusion protein of Fibroblast Growth Factor Receptor 2 (FGRF2) joined to periphilin 1, that occurs through a chromosomal translocation, is associated with intrahepatic cholangiocarcinoma; FGFR2-PPHLN1 activity requiring FGRF2-driven tyrosine kinase domain and PPHLN1 dimerization domain strongly drives cellular proliferation.
Jiyao W et al.(2023). "The conserved domain database in 2023.",