Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Jonathan M. Goodwin, William E. Dowdle, Rowena DeJesus, Zuncai Wang, Philip Bergman, Marek Kobylarz, Alicia Lindeman, Ramnik J. Xavier, Gregory McAllister, Beat Nyfeler, Gregory Hoffman, Leon O. Murphy
Iron is vital for many homeostatic processes, and its liberation from ferritin nanocages occurs in the lysosome. Studies indicate that ferritin and its binding partner nuclear receptor coactivator-4 (NCOA4) are targeted to lysosomes by a form of selective autophagy. By using genome-scale functional screening, we identify an alternative lysosomal transport pathway for ferritin that requires FIP200, ATG9A, VPS34, and TAX1BP1 but lacks involvement of the ATG8 lipidation machinery that constitutes classical macroautophagy. TAX1BP1 binds directly to NCOA4 and is required for lysosomal trafficking of ferritin under basal and iron-depleted conditions. Under basal conditions ULK1/2-FIP200 controls ferritin turnover, but its deletion leads to TAX1BP1-dependent activation of TBK1 that regulates redistribution of ATG9A to the Golgi enabling continued trafficking of ferritin. Cells expressing an amyotrophic lateral sclerosis (ALS)-associated TBK1 allele are incapable of degrading ferritin suggesting a molecular mechanism that explains the presence of iron deposits in patient brain biopsies.

Graphical abstract

Teaser

Goodwin et al. employ functional CRISPR screening approaches to show lysosomal ferritin turnover is autophagy-independent, revealing a role for TBK1 in iron homeostasis.


from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gJWEmE
via IFTTT