bims-unfpre 2020-01-05 papers

Issue of 2020–01–05
two papers selected by
Susan Logue, University of Manitoba

Diabetes. 2020 Jan 02. pii: db190984. [Epub ahead of print]

Beta-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Post-Transcriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1.

Sofia Thomaidou, Maria J L Kracht, Arno van der Slik, Sandra Laban, Eelco J de Koning, Francoise Carlotti, Rob C Hoeben, Bart O Roep, Arnaud Zaldumbide.

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CTL-mediated beta-cell destruction in Type 1 Diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in recent onset T1D patients. While the combined action of signal peptide peptidase and endoplasmic reticulum aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human beta cells that ER stress regulates ERAP1 gene expression at post-transcriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of beta cells to the immune system and position the IRE1α/miR-17 pathway as a central component in beta cell destruction processes and as potential target for the treatment of autoimmune T1D.

DOI: https://doi.org/10.2337/db19-0984

J Cell Biol. 2020 Feb 03. pii: e201908182. [Epub ahead of print]219(2):

Reticulon protects the integrity of the ER membrane during ER escape of large macromolecular protein complexes.

Yu-Jie Chen, Jeffrey M Williams, Peter Arvan, Billy Tsai.

Escape of large macromolecular complexes from the endoplasmic reticulum (ER), such as a viral particle or cellular aggregate, likely induces mechanical stress initiated on the luminal side of the ER membrane, which may threaten its integrity. How the ER responds to this threat remains unknown. Here we demonstrate that the cytosolic leaflet ER morphogenic protein reticulon (RTN) protects ER membrane integrity when polyomavirus SV40 escapes the ER to reach the cytosol en route to infection. SV40 coopts an intrinsic RTN function, as we also found that RTN prevents membrane damage during ER escape of a misfolded proinsulin aggregate destined for lysosomal degradation via ER-phagy. Our studies reveal that although ER membrane integrity may be threatened during ER escape of large macromolecular protein complexes, the action of RTN counters this, presumably by deploying its curvature-inducing activity to provide membrane flexibility and stability to limit mechanical stress imposed on the ER membrane.

DOI: https://doi.org/10.1083/jcb.201908182