PADI6: What we know about the elusive fifth member of the peptidyl arginine deiminase family

Abstract

Peptidyl arginine deiminase 6 (PADI6) is a maternal factor that is vital for early embryonic development. Deletion and mutations of its encoding gene in female mice or women lead to early embryonic developmental arrest, female infertility, maternal imprinting defects and hyperproliferation of the trophoblast. PADI6 is the fifth and least well-characterized member of the peptidyl arginine deiminases (PADIs), which catalyse the post-translational conversion of arginine to citrulline. It is less conserved than the other PADIs, and currently has no reported catalytic activity. While there are many suggested functions of PADI6 in the early mouse embryo, including in embryonic genome activation, cytoplasmic lattice formation, maternal mRNA and ribosome regulation, and organelle distribution, the molecular mechanisms of its function remain unknown. In this review, we discuss what is known about the function of PADI6 and highlight key outstanding questions that must be answered if we are to understand the crucial role it plays in early embryo development and female fertility. This article is part of the Theo Murphy meeting issue ‘The virtues and vices of protein citrullination’.

Citrullination: new tricks for an old mod

“…However, PADI6 has key roles in oocyte maturation and early embryonic development, with its loss leading to female infertility and early embryo arrest. Williams & Walport [ 25 ] contribute a comprehensive review on PADI6. In our quest to understand citrullination, it is important to consider the functions of PADI6 in the oocyte—while this is a highly specialized cell with unique biology, it is plausible that the non-catalytic functions of PADI6 are mirrored by other PADIs in different contexts.…”

GnRH Induces Citrullination of the Cytoskeleton in Murine Gonadotrope Cells

“…This reaction is catalyzed by a family of enzymes termed peptidylarginine deiminases (PADs or PADIs), which are composed of five isoforms: PAD1-4 and 6 [ 1 , 2 , 3 ]. Each PAD family member appears to have preferential catalytic targets for citrullination with the exception of PAD6, which lacks enzymatic activity [ 4 , 5 ]. PADs are expressed in a wide array of normal tissues such as the brain, skin, and female reproductive tissues, suggesting that citrullination also has an important function in regulating physiological processes [ 1 , 3 , 6 , 7 , 8 ].…”

A maternal-effectPadi6variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos

“…All SCMC proteins are encoded by maternal-effect genes. PADI6 is an oocyte-specific protein belonging to the peptidylarginine deiminase (PAD) protein family but without evident enzymatic activity in vitro ( Raijmakers et al 2007 ; Williams and Walport 2023 ). Maternal PADI6 is required for embryo development beyond the two-cell stage and formation of the oocyte lattices that are cytoplasmic structures believed to work as ribosomal storage for the early embryo ( Esposito et al 2007 ).…”

“…In humans, biallelic loss-of-function mutations of PADI6 are associated with female infertility and hydatidiform moles ( Qian et al 2018 ). Furthermore, both biallelic and monoallelic PADI6 variants have been found in the healthy mothers of children affected by genomic imprinting disorders ( Eggermann et al 2022 ; Williams and Walport 2023 ).…”