A guide to the rhomboid protein superfamily in development and disease.

Rhomboid proteins are considered to be the most widespread membrane proteins across all forms of life. This superfamily comprises both active intramembrane serine proteases that catalyze the release of factors from the membrane, and a eukaryotic subset of non-catalytic members in which rhomboid architecture supports deviating functions. Although rhomboid was discovered in genetic studies of insect development, rhomboid research has broadened dramatically over the past 15 years; rhomboid enzymes are now the best biophysically understood of all intramembrane proteases, and are considered promising therapeutic targets for diseases ranging from parasitic infections to Parkinsonian neurodegeneration. Perhaps the most rapid progress has come with the catalytically inert rhomboid proteins, some of which regulate protein trafficking and/or function, and their prominence is underscored by clinical mutations. Such a diverse collection of advances mark an excellent point to review the state of this vibrant area of research, not because central questions have been answered, but instead because a firm grip in key areas has been established, and the field is now poised for breakthroughs.