The cellular roles of rhomboid proteases fall into four categories. Top left: Rhomboid proteases initiate EGF signaling during Drosophila development. Rhomboid-1 is localized in the Golgi apparatus, and cleaves Spitz (green) after it is transported from the endoplasmic reticulum by Star (purple). Cleaved Spitz is secreted to activate EGF signaling in neighboring cells. Top right: The mitochondrial rhomboid PARL cleaves PINK1 to reduce Parkin recruitment to mitochondria and downregulate mitophagy. Cleavage may depend on changes in PINK1 topogenesis in response to mitochondrial potential. Bottom right: Malaria parasite-encoded rhomboid proteases cleave adhesins to disassemble the junction formed between parasite and host erythrocyte at the end of invasion. Note that adhesins (in black), initially held in internal organelles, encounter rhomboid only when they are secreted onto the surface and motored to the posterior of the parasite. Bottom left: The Providencia rhomboid protease AarA activates TatA by removing a small amino-terminal extension. This allows TatA to assemble into the machinery required for protein (and presumably quorum-sensing signal) export. In the left two roles rhomboid cleavage activates a latent factor whereas in the right two roles cleavage inactivates the target protein.