The mammalian rhomboid protein RHBDL4 protects against endoplasmic reticulum stress by regulating the morphology and distribution of ER sheets.

In metazoans, the architecture of the endoplasmic reticulum (ER) differs between cell types and undergoes major changes throughout the cell cycle and according to physiological needs. Although much is known about how the different ER morphologies are generated and maintained, especially ER tubules, how context-dependent changes in ER shape and distribution are regulated and the factors involved are less well characterized, as are the factors that contribute to the positioning of the ER within the cell. By overexpression and KO experiments, we show that the levels of RHBDL4, an ER-resident rhomboid protease, modulate the shape and distribution of the ER, especially during conditions that require rapid changes in the ER sheet distribution, such as ER stress. We demonstrate that RHBDL4 interacts with cytoskeleton-linking membrane protein 63 (CLIMP-63), a protein involved in ER sheet stabilization, as well as with the cytoskeleton. Furthermore, we found that mice lacking RHBDL4 are sensitive to ER stress and develop liver steatosis, a phenotype associated with unresolved ER stress. Taken together, these data suggest a new physiological role for RHBDL4 and also imply that this function does not require its enzymatic activity.

Substrates and physiological functions of secretase rhomboid proteases.

Rhomboids are conserved intramembrane serine proteases with widespread functions. They were the earliest discovered members of the wider rhomboid-like superfamily of proteases and pseudoproteases. The secretase class of rhomboid proteases, distributed through the secretory pathway, are the most numerous in eukaryotes, but our knowledge of them is limited. Here we aim to summarise all that has been published on secretase rhomboids in a concise encyclopaedia of the enzymes, their substrates, and their biological roles. We also discuss emerging themes of how these important enzymes are regulated.