On Tuesday morning, at the 2015 EMBO meeting in Birmingham, UK, I attended the session on the ER and protein folding. The session – organized by Manu Hegde – illuminated a lot of the molecular details of how proteins can be translocated into, or extracted from, the endoplasmic reticulum. Irmgard Sinning described the crystal structures of some of the RNA and proteins that make up the signal recognition particle, helping to explain how this complex can arrest the translation of nascent secretory proteins and deliver them, along with the ribosome to the ER membrane. Hegde, meanwhile, talked about how, once docked at the ER membrane, the ribosome-nascent chain complex might open up the translocon pore to allow the secretory protein’s passage into the ER.
Once inside the ER, proteins need to fold into the correct conformation and, if that proves impossible, they must be exported back into the cytosol and degraded. Kenji Inaba discussed how a protein called ERdj5 promotes ER-associated degradation (ERAD) by reducing incorrect disulfide bonds in misfolded proteins. And Dick van den Boomen, from Paul Lehner’s laboratory, described how the ERAD pathway can be hijacked by human cytomegalovirus to induce the degradation of certain host proteins, such as the MHC Class I molecule.
The session followed on from Monday’s keynote lecture by Peter Walter, who presented a wonderful example of how basic, curiosity-driven research can quickly lead to unexpected clinical applications.
Walter and colleagues initially screened for small molecule inhibitors to block the PERK pathway, a component of the Unfolded Protein Response to ER stress that reduces general protein translation while upregulating the translation of a transcription factor, ATF4, that can help cells either adapt to this stress or undergo apoptosis. The researchers identified a molecule called ISRIB, which blocked ATF4 induction and restored general translation by boosting the activity of the translation initiation factor eIF2a. The activity of this initiation factor is implicated in memory consolidation and, remarkably, ISRIB enhances learning and memory in mice by inhibiting long-term depression. ISRIB has quite favorable pharmacological properties, and Walter thinks that it might be able to treat a variety of cognitive disorders in humans. A serendipitous discovery, for sure, but one that highlights the importance of basic cell biological research.