iRHOM2: A Regulator of Palmoplantar Biology, Inflammation, and Viral Susceptibility

Abstract

The palmoplantar epidermis is a specialized area of the skin that undergoes high levels of mechanical stress. The palmoplantar keratinization and esophageal cancer syndrome, tylosis with esophageal cancer, is linked to mutations in RHBDF2 encoding the proteolytically inactive rhomboid protein, iRhom2. Subsequently, iRhom2 was found to affect palmoplantar thickening to modulate the stress keratin response and to mediate context-dependent stress pathways by p63. iRhom2 is also a direct regulator of the sheddase, ADAM17, and the antiviral adaptor protein, stimulator of IFN genes. In this perspective, the pleiotropic functions of iRhom2 are discussed with respect to the skin, inflammation, and the antiviral response.

Figure 1

Differential expression of K16 in palm epidermis. Immunofluorescent staining of human palm skin using mouse monoclonal anti-K16 antibody (clone: LL025, green). Nuclei counterstained with DAPI (blue). The boundary between stratum granulosum and stratum corneum is indicated by a dashed white line to highlight the Rs and Fs that constitute palmoplantar skin. K16 expression is high in KCs located in the F and greatly reduced or absent in KCs in the R. Bar = 50 μm. F, furrow; K16, keratin 16; KC, keratinocyte; R, ridge.

Figure 2

The interdependence of iRhom2 and ADAM17 in proinflammatory signaling pathways and upregulation of iRhom2, ADAM17, and STING mRNA in murine viral infection. (a) iRhom2 is required for trafficking pro-ADAM17 from the ER to the Golgi where Furin removes the ADAM17 inhibitory prodomain. Mature ADAM17 complexes with iRhom2 at the plasma membrane where it cleaves and releases soluble mediators including IL-6R and TNF-α. (b) Immunostaining showed reduced iRhom2 expression in ADAM17-deficient skin to that of the control. Bar = 100 μm; n = 1. (c) Boxplots showing the expression of Rhbdf2 (iRhom2), Adam17, and Tmem173 (STING) in murine lung tissue infected with (i) influenza A (n = 18) or (ii) RSV (n = 20) (GSE119853; Barrett et al., 2013; Singhania et al., 2019). ∗∗∗P ≤ 0.001, ∗∗∗∗P ≤ 0.0001 (Student’s t-test). ER, endoplasmic reticulum; IL-6R, IL-6 receptor; RSV, respiratory syncytial virus; STING, stimulator of IFN genes; TNFR, TNF receptor.