Bacterial rhomboid proteases mediate quality control of orphan membrane proteins

Abstract

Although multiprotein membrane complexes play crucial roles in bacterial physiology and virulence, the mechanisms governing their quality control remain incompletely understood. In particular, it is not known how unincorporated, orphan components of protein complexes are recognised and eliminated from membranes. Rhomboids, the most widespread and largest superfamily of intramembrane proteases, are known to play key roles in eukaryotes. In contrast, the function of prokaryotic rhomboids has remained enigmatic. Here, we show that the Shigella sonnei rhomboid proteases GlpG and the newly identified Rhom7 are involved in membrane protein quality control by specifically targeting components of respiratory complexes, with the metastable transmembrane domains (TMDs) of rhomboid substrates protected when they are incorporated into a functional complex. Initial cleavage by GlpG or Rhom7 allows subsequent degradation of the orphan substrate. Given the occurrence of this strategy in an evolutionary ancient organism and the presence of rhomboids in all domains of life, it is likely that this form of quality control also mediates critical events in eukaryotes and protects cells from the damaging effects of orphan proteins.

Derlins with scissors: primordial ERAD in bacteria

“…As stated above, PARL too forms a functional unit with a AAA ATPase, YME1L (Wai et al , ). Taken together, the bacterial “primordial ERAD‐like” degradation systems identified by Began et al () and Liu et al () may indicate that rhomboids have initially emerged to assist membrane protein quality control and degradation, and subsequently evolved to take over other functions, including the originally described limited proteolysis in growth factor activation.…”

“…This has led to the question of what the conserved, primordial role of rhomboids is. In light of the studies by Began et al () and Liu et al (), protein degradation now emerges as the conserved function (Fig ). Showing high similarity to bacterial rhomboids, the mitochondrial rhomboid protease PARL has been demonstrated to assemble with the AAA protease YME1L to regulate processing and turnover of the protein kinase PINK1 and the phosphatase PGAM5 (Wai et al , ).…”

“…Began et al () report a previously uncharacterized function for the Bacillus subtilis rhomboid protease YqgP in the degradation of the magnesium transporter MgtE, both by direct cleavage and by acting as a substrate adaptor for the AAA protease FtsH. Liu et al (), studying the Shigella sonnei rhomboid proteases GlpG and Rhom7 (a new rhomboid that had not been characterized before), identified subunits of respiratory complexes as rhomboid substrates. Although there is an apparent similarity—both being bacterial rhomboids degrading membrane proteins—the molecular and functional differences are remarkable.…”

“…Furthermore, both reports reveal striking differences in substrate recognition. GlpG and Rhom7 detect unstable transmembrane domains, originating from a characteristic proline residue that, in the absence of complex partners, destabilizes the membrane anchor (Liu et al , ). YqgP seems not to require such a distinct substrate feature.…”

“…As such, RHBDL4 triggers removal of orphan pre‐T‐cell receptor subunits (Fleig et al , ) and the oligosaccharide transferase complex (Knopf et al , ). Interestingly, rhomboid‐mediated degradation also shows conservation from a physiological point of view, as regulation of energy metabolism is a feature observed in both Shigella (Liu et al , ) and mitochondria (Spinazzi et al , ). To some extent, even the tuning of glycosylation by RHBDL4 in the ER (Knopf et al , ) may be functionally paralleled by an archaeal rhomboid protease, Haloferax volcanii RhoII (Parente et al , ).…”