Regulation of ribosome detachment from the mammalian endoplasmic reticulummembrane

In current models, protein translocation in the endoplasmic reticulum (ER) occurs in the context of two cycles, the signal recognition particle (SRP) cycle and the ribosome cycle. Both SRP and ribosomes bind to the ER membran e as a consequence of the targeting process of translocation. Whereas SRP r elease from the ER membrane is regulated by the GTPase activities of SRP an d the SRP receptor, ribosome release from the ER membrane is thought to occ ur in response to the termination of protein synthesis. We report that ER-b ound ribosomes remain membrane-bound following the termination of protein s ynthesis and in the bound state can initiate the translation of secretory a nd cytoplasmic proteins. Two principal observations are reported. 1) Membra ne-bound ribosomes engaged in the synthesis of proteins lacking a signal se quence are released from the ER membrane as ribosome-nascent polypeptide co mplexes. 2) Membrane-hound ribosomes translating secretory proteins can acc ess the translocon in an SRP receptor-independent manner. We propose that r ibosome release from the ER membrane occurs in the context of protein trans lation, with release occurring by default in the absence of productive nasc ent polypeptide-membrane interactions.