Maturation of Lipophagic Organelles in Hepatocytes Is Dependent Upon a Rab10/Dynamin-2 Complex.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
30
04
2019
accepted:
14
11
2019
pubmed:
7
12
2019
medline:
30
4
2021
entrez:
7
12
2019
Statut:
ppublish
Résumé
Hepatocytes play a central role in storage and utilization of fat by the liver. Selective breakdown of lipid droplets (LDs) by autophagy (also called lipophagy) is a key process utilized to catabolize these lipids as an energy source. How the autophagic machinery is selectively targeted to LDs, where it mediates membrane engulfment and subsequent degradation, is unclear. Recently, we have reported that two distinct GTPases, the mechanoenzyme, dynamin2 (Dyn2), and the small regulatory Rab GTPase, Rab10, work independently at distinct steps of lipophagy in hepatocytes. In an attempt to understand how these proteins are regulated and recruited to autophagic organelles, we performed a nonbiased biochemical screen for Dyn2-binding partners and found that Dyn2 actually binds Rab10 directly through a defined effector domain of Rab10 and the middle domain of Dyn2. These two GTPases can be observed to interact transiently on membrane tubules in hepatoma cells and along LD-centric autophagic membranes. Most important, we found that a targeted disruption of this interaction leads to an inability of cells to trim tubulated cytoplasmic membranes, some of which extend from lipophagic organelles, resulting in LD accumulation. This study identifies a functional, and direct, interaction between Dyn2 and a regulatory Rab GTPase that may play an important role in hepatocellular metabolism.
Sections du résumé
BACKGROUND AND AIMS
Hepatocytes play a central role in storage and utilization of fat by the liver. Selective breakdown of lipid droplets (LDs) by autophagy (also called lipophagy) is a key process utilized to catabolize these lipids as an energy source. How the autophagic machinery is selectively targeted to LDs, where it mediates membrane engulfment and subsequent degradation, is unclear. Recently, we have reported that two distinct GTPases, the mechanoenzyme, dynamin2 (Dyn2), and the small regulatory Rab GTPase, Rab10, work independently at distinct steps of lipophagy in hepatocytes.
APPROACH AND RESULTS
In an attempt to understand how these proteins are regulated and recruited to autophagic organelles, we performed a nonbiased biochemical screen for Dyn2-binding partners and found that Dyn2 actually binds Rab10 directly through a defined effector domain of Rab10 and the middle domain of Dyn2. These two GTPases can be observed to interact transiently on membrane tubules in hepatoma cells and along LD-centric autophagic membranes. Most important, we found that a targeted disruption of this interaction leads to an inability of cells to trim tubulated cytoplasmic membranes, some of which extend from lipophagic organelles, resulting in LD accumulation.
CONCLUSIONS
This study identifies a functional, and direct, interaction between Dyn2 and a regulatory Rab GTPase that may play an important role in hepatocellular metabolism.
Identifiants
pubmed: 31808574
doi: 10.1002/hep.31059
pmc: PMC8919976
mid: NIHMS1766358
doi:
Substances chimiques
Rab10 protein, rat
0
rab GTP-Binding Proteins
EC 3.6.5.2
Dynamin II
EC 3.6.5.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
486-502Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK044650
Pays : United States
Organisme : NIAAA NIH HHS
ID : 5RO1AA020735
Pays : United States
Organisme : NIDDK NIH HHS
ID : 5R37DK044650
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA020735
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK084567
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK044650
Pays : United States
Informations de copyright
© 2020 by the American Association for the Study of Liver Diseases.
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