Check out the Ithaca murals website if you haven’t visited it already. Caleb et al. have done a wonderful job putting together a murals map that you could refer to. Great idea for organizing a group mural walk/ bike ride! Ithaca murals website link
Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity.
Kayatekin et. al., Cell 173, 1-12, March 2018
Islet amyloid polypeptide (IAPP) is a small peptide secreted by the pancreatic β islet cells. It is thought to regulate the function of the islet cells by inhibiting insulin secretion. It was discovered (and named) due to its tendency to aggregate into insoluble amyloid fibrils in patients with type 2 diabetes (T2D). Subsequent work showed that the cytotoxicity was contributed by smaller, intracellular oligomeric intermediates of IAPP, not the mature amyloid fibrils. Yet what aspect of cellular biology is impacted by these toxic oligomers has remained unclear.
Kayatekin and colleagues report that IAPP-induced proteotoxicity is in part contributed by the clogging of the endoplasmic reticulum (ER) translocon, and can be rescued by translocon associated transmembrane protease Ste24 in yeast or its human homolog ZMPSTE24. Ste24/ZMPSTE24 were recently discovered to directly interact with clogged translocons and cleave jammed proteins.
In order to understand IAPP toxicity, the authors took advantage of the cell death associated with the expression of an oligomeric version of the IAPP peptide in budding yeast, Saccharomyces cerevisiae. Using complementary genetic screens the authors found that functional Ste24 protease was critical for alleviating IAPP toxicity in yeast. The suppression by Ste24 was specific to IAPP and did not mitigate the toxicity caused by other aggregation prone proteins such as α-synuclein or TDP-43. Emphasizing the conservation of the declogging function, overexpression of the human homolog ZMPSTE24 in yeast lacking Ste24 could efficiently rescue IAPP toxicity. Using their yeast model for assaying declogging capability, the authors analyzed 111 ZMPSTE24 single nucleotide polymorphisms discovered in T2D patients and non-diabetic controls and found an enrichment of loss-of-function mutations among people with T2D (although somewhat mild).
Finally got around to putting this website together. It is powered by Jekyll using Friday theme and I can use Markdown to author my posts. It is styled almost entirely with Bootstrap 4. It actually is a lot easier than I thought it was going to be. I’ll write up my experience in more detail later with instructions and links that I found useful.