New research led by Dr Iqbal Dulloo, a senior postdoctoral researcher in Matthew Freeman’s lab at the Dunn School of Pathology, has uncovered a previously unknown signalling pathway between the endoplasmic reticulum (ER) and the nucleus, involving the pseudoprotease iRhom2.
Key findings of this study were published online on 5 January 2024 in Molecular Cell, titled “Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway”.
The research demonstrates that the polytopic iRhom2 protein, known for its role in regulating growth factor and inflammatory signalling pathways, is a non-canonical substrate of the signal peptidase complex (SPC), and acquires an unexpected function in the nucleus following proteolytic cleavage.
The cleaved N-terminal domain of iRhom2 translocates to the nucleus, leading to changes in the cellular transcriptome. Elevated levels of nuclear iRhom2 were observed in various human skin pathologies such as lesional psoriasis, suggesting potential disease association.
Dr Dulloo believes the research is significant as it sheds light on a new mechanism of action for iRhom pseudoproteases. Unlike their previous functions which are associated with the recognition of transmembrane domains of their client proteins, this research uncovers an unexpected feature of iRhoms as substrates of the SPC, contributing to a more comprehensive understanding of their role in intracellular signalling.
The study also highlights the importance of pseudoenzymes, present in many enzyme families, but yet often neglected relative to their active counterparts. This new role of iRhom pseudoproteases further exemplify these proteins as essential regulators of intracellular signalling pathways.
The conventional belief regarding the primary function of the signal peptidase complex is also questioned. Traditionally associated with removing signal peptides, SPC is shown here to have a more diverse and complex role in cellular signalling.
Dr Dulloo commented: “This project has been a labour of love to say the least, highly risky and getting binned a few times along the way, but I’m delighted that in the end, the findings turned out to be quite unexpected, exciting and potentially significant for several fields of research.”