SPP pulls an inside job

Aprotease helps cells dispose of certain ER proteins by cleaving them within the organelle’s membrane, Boname et al. reveal.

Cells send damaged or unneeded ER proteins back to the cytosol for destruction by the proteasome. A key step in this process is ubiquitylation of the doomed protein by ubiquitin ligases such as TRC8. TRC8 interacts with an enzyme known as signal peptide peptidase (SPP), whose best-known job is cutting signal peptides in their transmembrane domain, allowing them to escape from the ER. But SPP’s interaction with TRC8 suggested that it also participates in the removal of ER proteins.

Boname et al. performed a proteomics screen to identify ER membrane proteins that build up in cells lacking SPP. Their analysis suggested that heme oxygenase-1 (HO-1), an enzyme that breaks down heme, is one of SPP’s targets. The team tested that possibility by steeping the cells in hemin, which spurs HO-1 production. After hemin’s removal, HO-1 levels fell more slowly in cells lacking SPP than in controls.

HO-1 is a tail-anchored protein, embedded in the ER membrane with only the nub of its C terminus protruding into the lumen. SPP cut HO-1 in its transmembrane domain, after which TRC8 stepped in to ubiquitylate the severed protein. The researchers determined that SPP cleaved three other tail-anchored proteins in their transmembrane domains and promoted their subsequent degradation. However, SPP didn’t attack another tail-anchored ER protein the team tested.

SPP and TRC8 might collaborate to extract target proteins from the ER membrane so that they can meet their fate in the proteasome. Whether SPP helps cells rid themselves of the majority of tail-anchored proteins, which constitute up to 5% of membrane proteins, remains to be seen.