Acidic domain of WRNp is critical for autophagy and up-regulates age associated proteins.

Impaired autophagy may be associated with normal and pathological aging. Here we explore a link between autophagy and domain function of Werner protein (WRNp). Werner (WRN) mutant cell lines AG11395, AG05229 and normal aged fibroblast AG13129 display a deficient response to tunicamycin mediated endoplasmic reticulum (ER) stress induced autophagy compared to clinically unaffected GM00637 and normal young fibroblast GM03440. Cellular endoplasmic reticulum (ER) stress mediated autophagy in WS and normal aged cells is restored after transfection with wild type full length WRN, but deletion of the acidic domain from wild type WRN fails to restore autophagy. The acidic domain of WRNp was shown to regulate its transcriptional activity, and here, we show that it affects the transcription of certain proteins involved in autophagy and aging. Furthermore, siRNA mediated silencing of WRN in normal fibroblast WI-38 resulted in decrease of age related proteins Lamin A/C and Mre11.