Lipid-binding proteins in autophagy

Defects in autophagy are linked to several diseases (as cancer, neurodegeneration and Crohns disease) and aging. Characterization of the molecular mechanisms of autophagy is thus a topic of intense investigation as such insight may pave the way for the development of specific autophagy-modulating drugs, which could effectively treat or even cure many devastating diseases. Recently, our understanding of the hierarchy of autophagy-related proteins have increased significantly, but very little is known about the lipids involved, their interaction with the autophagic protein machinery and how these are regulated under various metabolic conditions and in disease.

About the project

This project aims to identify and characterize novel lipid-binding proteins involved in non-selective and selective types of autophagy. Such proteins are identified through siRNA screens, using a library targeting human lipid-binding proteins in cells with inducible expression of various EGFP-mCherry tagged autophagic cargo, followed by automated imaging and quantification. Candidate proteins that either stimulate or inhibit autophagy are further analyzed for the mechanisms involved and their link to disease using various in vitro and in vivo models as shown above.

Outcomes/Recent findings

  • Membrane remodeling by the PX-BAR protein SNX18 promotes autophagosome formation (PMID: 23878278)
  • HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels (PMID: 28004827)
  • SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting Dynamin-2 (PMID: 29437695).
  • Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes (PMID: 30778222).

Financing

  • The University of Oslo
  • The Research Council of Norway
  • The Norwegian Cancer Society
  • EU H-2020 MSCA COFUND and ITN actions
Published Dec. 9, 2019 1:22 PM - Last modified Dec. 9, 2019 1:22 PM