Proteomic Identification of in Vivo Interactors Reveals Novel Function of Skin Cornification Proteins

Protection against injurious external insults and loss
of vital
fluids is essential for life and is in all organisms, from bacteria
to plants and humans, provided by some form of barrier. Members of
the small proline-rich (SPRR) protein family are major components
of the cornified cell envelope (CE), a structure responsible for the
barrier properties of our skin. These proteins are efficient reactive
oxygen species (ROS) quenchers involved not only in the establishment
of the skin’s barrier function but also in cell migration and
wound healing. Here, a proteomic analysis of in vivo SPRR-interacting proteins confirmed their function in CE-formation
and ROS-quenching and also revealed a novel unexpected role in DNA-binding.
Direct in vitro and in vivo evidence
proved that the DNA-binding capacity of SPRRs is regulated by the
oxidation state of the proteins. At low ROS levels, nuclear SPRR is
able to bind DNA and prevent ROS-induced DNA damage. When ROS levels
increase, SPRR proteins multimerize and form an effective antioxidant
barrier at the cell periphery, possibly to prevent the production
or infiltration of ROS. At even higher ROS exposure, DNA-binding is
restituted. A molecular model explaining how the intracellular oxidation
state of SPRRs likely influences their selective protective function
is provided.