Title: Unraveling the novel role of iRHOM2 in the nucleus
Funder: The Academy of Medical Sciences

Abstract: Terminal differentiation (epidermal barrier) allows the skin to respond to a number of environmental stressors. Common (psoriasis) and rare (ichthyoses) human skin diseases show a range of epidermal barrier defects including aberrant keratinization, hyperproliferation or inflammation. Human gain-of-function mutations in iRHOM2 are associated with the inherited syndrome Tylosis with Oesophageal Cancer which presents with a focal palmoplantar keratoderma and a high lifetime risk of squamous oesophageal cancer. I recently reported that iRHOM2 is a novel target gene of p63, and that both p63 and iRHOM2 differentially regulate cell survival and oxidative stress signalling pathways in normal and hyperproliferative keratinocytes. Moreover, my unpublished data revealed that an unreported 55kDa N-terminal fragment of iRHOM2 (p55iRHOM2) is capable of translocating into the nucleus, and this localisation is particularly pronounced in stressed keratinocytes. I hypothesise that mechanical stress or epidermal trauma stress accelerates iRHOM2 processing and nuclear localisation to affect p63 signalling and the transcriptomic regulation of epidermal homeostasis. I will explore the role of nuclear iRHOM2 in gene regulation through ChIP-seq and RNA-seq analyses in normal human keratinocytes. By combining proteomics and siRNA approaches, I aim to characterize the fundamental biology of nuclear iRHOM2 and investigate interlinking pathways with the identification of novel interacting protein partners. This work will provide novel molecular mechanisms controlled by nuclear iRHOM2 in skin differentiation and its relationship with skin barrier defects observed in pathologies. This proposal will provide critical insight for the potential development of new therapies associated with hyperproliferative/inflammatory disorders mediated mediated by nuclear iRHOM2.

Lay abstract: The skin covers the body and forms a protective barrier against the surrounding environment, bacteria and injuries. A breach in the barrier affects the epidermal barrier and results in skin disorders such as psoriasis, eczema, atopic dermatitis or ichthyoses. These skin conditions are often associated with a stressed and thicker epidermis and resulting in significant negative quality-of-life effects. Although there are several treatment options available, understanding the triggers of these pathologies and identifying new treatment strategies are still needed. My research intends to investigate the role of a protein called iRHOM2 in skin homeostasis as it may be considered as a key regulator of the epidermal thickness and this will help to understand how its deregulation could lead to skin pathologies. I discovered a novel form of this protein, called p55iRHOM2 that may play unknown key roles. In order to reveal its novel function, I will use a range of molecular and cellular tools in skin cells to track p55iRHOM2. This work will help to understand in more details the stress signals and cellular processes regulated by p55iRHOM2 in the skin and explain its correlation with the disease. This will give us the knowledge to understand how the p55iRHOM2 coud influence disease outcome in patients. This will enable the development of future therapies in stressed skin (in common and rare human skin conditions) and improve patient conditions.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: SKIN;CANCER AND NEOPLASMS