A novel Rab10-EHBP1-EHD2 complex essential for the autophagic engulfment of lipid droplets
Zhipeng Li,Ryan J. Schulze,Shaun G. Weller,Eugene W. Krueger,Micah B. Schott,Xiaodong Zhang,Carol A. Casey,Jun Liu,Jacqueline Stöckli,David E. James,Mark A. McNiven +10 more
TL;DR: A novel function for a small Rab guanosine triphosphatase (GTPase) in the recruitment of adaptors required for the engulfment of LDs by the growing autophagosome is reported.
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Abstract: The autophagic digestion of lipid droplets (LDs) through lipophagy is an essential process by which most cells catabolize lipids as an energy source. However, the cellular machinery used for the envelopment of LDs during autophagy is poorly understood. We report a novel function for a small Rab guanosine triphosphatase (GTPase) in the recruitment of adaptors required for the engulfment of LDs by the growing autophagosome. In hepatocytes stimulated to undergo autophagy, Rab10 activity is amplified significantly, concomitant with its increased recruitment to nascent autophagic membranes at the LD surface. Disruption of Rab10 function by small interfering RNA knockdown or expression of a GTPase-defective variant leads to LD accumulation. Finally, Rab10 activation during autophagy is essential for LC3 recruitment to the autophagosome and stimulates its increased association with the adaptor protein EHBP1 (EH domain binding protein 1) and the membrane-deforming adenosine triphosphatase EHD2 (EH domain containing 2) that, together, are essential in driving the activated “engulfment” of LDs during lipophagy in hepatocytes.
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Citations
LRRK2 activation in idiopathic Parkinson’s disease
Roberto Di Maio,Eric K. Hoffman,Emily M. Rocha,Matthew T. Keeney,Laurie H. Sanders,Laurie H. Sanders,Briana R. De Miranda,Alevtina Zharikov,Amber D. Van Laar,Antonia F. Stepan,Thomas A. Lanz,Julia Kofler,Edward A. Burton,Dario R. Alessi,Teresa G. Hastings,J. Timothy Greenamyre +15 more
TL;DR: In postmortem brain tissue from individuals with idiopathic PD (iPD), LRRK2 kinase activity is aberrantly increased in vulnerable nigrostriatal dopamine neurons, suggesting that L RRK2 Kinase inhibitors may be useful for treating patients with iPD and PD patients carrying LRRk2 mutations.
A Proximity Labeling Strategy Provides Insights into the Composition and Dynamics of Lipid Droplet Proteomes
Kirill Bersuker,Clark W.H. Peterson,Milton To,Steffen J. Sahl,Victoria Savikhin,Elizabeth A. Grossman,Daniel K. Nomura,James A. Olzmann +7 more
TL;DR: A proximity labeling strategy that exploits LD-targeted APEX2 to biotinylate LD proteins in living cells identified the vast majority of previously validated LD proteins, excluded common contaminating proteins, and revealed new LD proteins.
301
Watch What You (Self-) Eat: Autophagic Mechanisms that Modulate Metabolism.
TL;DR: The metabolic signals that activate autophagy and metabolism, the mechanisms involved, and the downstream effects and implications while recognizing yet unanswered questions are outlined.
238
The ménage à trois of autophagy, lipid droplets and liver disease.
Yasmina Filali-Mouncef,Catherine Hunter,Catherine Hunter,Federica Roccio,Stavroula Zagkou,Nicolas Dupont,Charlotte Primard,Tassula Proikas-Cezanne,Tassula Proikas-Cezanne,Fulvio Reggiori +9 more
TL;DR: In this paper, the authors provided an overview on the biogenesis and functions of lipid droplets and the mechanisms underlying their lysosomal turnover by autophagic processes and focused on non-alcoholic steatohepatitis (NASH), a specific type of FLD characterized by steatosis, chronic inflammation and cell death.
218
Breaking fat: The regulation and mechanisms of lipophagy
TL;DR: A review of recent work focusing on LDs and lipophagy as well as highlighting challenges and future directions of research as the understanding oflipophagy continues to grow and evolve is summarized.
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References
Rab8a-AS160-MSS4 Regulatory Circuit Controls Lipid Droplet Fusion and Growth
Lizhen Wu,Dijin Xu,Linkang Zhou,Bingxian Xie,Li Yu,Hongyuan Yang,Lei Huang,Jing Ye,Haiteng Deng,Y. Adam Yuan,Shuai Chen,Peng Li +11 more
TL;DR: Rab8a is identified as a direct interactor and regulator of Fsp27 in mediating LD fusion in adipocytes and MSS4 antagonizes Fsp 27-mediated LD fusion activity through Rab8a, revealing a mechanistic signaling circuit controlling LD fusion and fatty liver formation.
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β-adrenergic receptor-stimulated lipolysis requires the RAB7-mediated autolysosomal lipid degradation.
TL;DR: The results showed a contribution of lipophagy to both basal and hormone-stimulated lipolysis and that RAB7 plays a pivotal role in the regulation of this autolysosome-mediated lipid degradation in fat cells.
115
EHBP-1 functions with RAB-10 during endocytic recycling in Caenorhabditis elegans.
Anbing Shi,Carlos Chih Hsiung Chen,Riju Banerjee,Doreen R. Glodowski,Anjon Audhya,Christopher Rongo,Barth D. Grant +6 more
TL;DR: Caenorhabditis elegans RAB-10 functions in endocytic recycling in polarized cells, regulating basolateral Cargo transport in the intestinal epithelia and postsynaptic cargo transport in interneurons, and a requirement for EHBP-1 in R AB-10–regulated transport in both of these tissues is demonstrated.
Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington's disease
Paul Richards,C Didszun,Susanna Campesan,A Simpson,B Horley,Kenneth W. Young,P Glynn,Kelvin Cain,Charalambos P. Kyriacou,Flaviano Giorgini,Pierluigi Nicotera,Pierluigi Nicotera +11 more
TL;DR: It is shown that dendritic spines are lost in the proximity of htt aggregates because of functional defects in local endosomal recycling mediated by the Rab11 protein, consistent with the model that mutant htt aggregation increases local autophagic activity, thereby sequestering Rab11 and diverting spine-forming cargo from RE into enlarged amphisomes.
Depletion of Rab32 decreases intracellular lipid accumulation and induces lipolysis through enhancing ATGL expression in hepatocytes.
TL;DR: It is shown that Rab32, the only Rab GTPase located in mitochondria, participates in hepatic steatosis and that ablation of Rab32 can induce intracellular lipolysis by enhancing the expression of adipose triglyceride lipase (ATGL), a key enzyme on the surface of lipid droplets which has been proved to be significant in controlling intrACEllular lipid accumulation.
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