Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity

Publication date: Available online 8 March 2018 Source:Cell Author(s): Can Kayatekin, Audra Amasino, Giorgio Gaglia, Jason Flannick, Julia M. Bonner, Saranna Fanning, Priyanka Narayan, M. Inmaculada Barrasa, David Pincus, Dirk Landgraf, Justin Nelson, William R. Hesse, Michael Costanzo, Chad L. Myers, Charles Boone, Jose C. Florez, Susan Lindquist Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to β cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to degrade peptides stuck within the translocon between the cytoplasm and the endoplasmic reticulum, was the strongest suppressor of IAPP toxicity. By testing variants of the human homolog, ZMPSTE24, with varying activity levels, the rescue of IAPP toxicity proved to be directly proportional to the declogging efficiency. Clinically relevant ZMPSTE24 variants identified in the largest database of exomes sequences derived from T2D patients were characterized using the yeast model, revealing 14 partial loss-of-function variants, which were enriched among diabetes patients over 2-fold. Thus, clogging of the translocon by IAPP oligomers may contribute to β cell failure. Graphical abstract Teaser A combination of yeast- and human-genetics studies explains how aggregates of hum...

Source: Cell - March 9, 2018 Category: Cytology Source Type: research