Inefficient Translocation of Preproinsulin Contributes to Pancreatic Beta Cell Failure and Late Onset Diabetes [Cell Biology]

April 25th, 2014 by Guo, H., Xiong, Y., Witkowski, P., Cui, J., Wang, L.-j., Sun, J., Lara-Lemus, R., Haataja, L., Hutchison, K., Shan, S.-o., Arvan, P., Liu, M.

Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of beta cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of positive charge in the n-region of its signal sequence) contributes to beta cell failure and diabetes. Specifically, we find that after targeting to the ER membrane, preproinsulin signal peptide (SP) mutants associated with autosomal dominant late-onset diabetes fail to be fully translocated across the ER membrane. The newly synthesized untranslocated preproinsulin remains strongly associated with the ER membrane, exposing its proinsulin moiety to the cytosol. Rather than accumulating in the ER and inducing ER stress, untranslocated preproinsulin accumulates in a juxtanuclear compartment distinct from the Golgi complex, induces the expression of heat shock protein 70 (HSP70), and promotes beta cell death. Restoring N-terminal positive charge to the mutant preproinsulin SP significantly improves the translocation defect. These findings not only reveal a novel molecular pathogenesis of beta cell failure and diabetes, but also provide the first evidence of the physiological and pathological significance of the SP n-region positive charge of secretory proteins.