Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100

Amengual, Jaume; Guo, Liang; Strong, Alanna; Madrigal‐Matute, Julio; Wang, Haizhen; Kaushik, Susmita; Brodsky, Jeffrey L.; Rader, Daniel J.; Cuervo, Ana María; Fisher, Edward A.

doi:10.1161/circresaha.117.311240

Cited by 39 publications

(41 citation statements)

References 58 publications

(98 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More recently, it was shown that ATZ was delivered for lysosomal degradation after transport through the secretory pathway but was then recognized in an autophagy‐like manner, that is, one that required an ER‐phagy receptor complex . It is noteworthy that aggregated forms of ApoB, which arise when cells are treated with oxidizing agents such as polyunsaturated fatty acids, are delivered from the Golgi via autophagolysosomes for degradation in the lysosome . Similarly, degradation and refolding of the W1282X mutant appear to be modulated by small molecules that regulate the autophagy pathway as well as proteasome activity .…”

Section: Discussionmentioning

confidence: 99%

Hsp104 facilitates the endoplasmic‐reticulum–associated degradation of disease‐associated and aggregation‐prone substrates

et al. 2019

Self Cite

View full text Add to dashboard Cite

Misfolded proteins in the endoplasmic reticulum (ER) are selected for ER-associated degradation (ERAD). More than 60 disease-associated proteins are substrates for the ERAD pathway due to the presence of missense or nonsense mutations. In yeast, the Hsp104 molecular chaperone disaggregates detergent-insoluble ERAD substrates, but the spectrum of diseaseassociated ERAD substrates that may be aggregation prone is unknown. To determine if Hsp104 recognizes aggregation-prone ERAD substrates associated with human diseases, we developed yeast expression systems for a hydrophobic lipid-binding protein, apolipoprotein B (ApoB), along with a chimeric protein harboring a nucleotide-binding domain from the cystic fibrosis transmembrane conductance regulator (CFTR) into which disease-causing mutations were introduced. We discovered that Hsp104 facilitates the degradation of ER-associated ApoB as well as a truncated CFTR chimera in which a premature stop codon corresponds to a disease-causing mutation. Chimeras containing a wild-type version of the CFTR domain or a different mutation were stable and thus Hsp104 independent. We also discovered that the detergent solubility of the unstable chimera was lower than the stable chimeras, and Hsp104 helped retrotranslocate the unstable chimera from the ER, consistent with disaggregase activity. To determine why the truncated chimera was unstable, we next performed molecular dynamics simulations and noted significant unraveling of the CFTR nucleotide-binding domain. Because human cells lack Hsp104, Additional Supporting Information may be found in the online version of this article.Lynley M. Doonan, Christopher J. Guerriero, and G. Michael Preston contributed equally to this work.Significance statement: Misfolded proteins can aggregate, which impairs cellular homeostasis and can give rise to disease. Although yeast express an enzyme that dissolves aggregates, humans lack this protein. We show that human aggregation-prone proteins associated with the endoplasmic reticulum are substrates for the yeast disaggregase. These data suggest that a human analog of the yeast disaggregase exists or that another mechanism removes aggregates associated with the endoplasmic reticulum.these data indicate that an alternate disaggregase or mechanism facilitates the removal of aggregation-prone, disease-causing ERAD substrates in their native environments.

show abstract

Section: Discussionmentioning

confidence: 99%

Hsp104 facilitates the endoplasmic‐reticulum–associated degradation of disease‐associated and aggregation‐prone substrates

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…ApoB labeling was performed as previously described (16). Briefly, McA hepatocytes were preincubated for 2 hours in amino acid-starvation medium (DMEM without methionine/cysteine, 1% FBS, 1% Lglutamine and Penicillin/Streptomycin).…”

Section: Cell Culture Experiments -Steady-state Labeling Studies and mentioning

confidence: 99%

β-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice

Zhou

Pinos

et al. 2020

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of cardiovascular diseases (CVDs), and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affect atherosclerosis progression in the atheroprone low-density lipoprotein receptor (LDLR) - deficient mice. In comparison to control-fed Ldlr-/- mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in Ldlr-/-/Bco1-/- mice, despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.

show abstract

“…The transmembrane receptor sorting protein sortilin was also recently discovered to bind ApoB and target it for autophagic degradation, resulting in reduced LDL secretion. This may be one mechanism by which a known genetic polymorphism increasing sortilin expression substantially lowers circulating LDL levels [56]. At the receiving end, lipoproteins are endocytosed in some cell types including macrophages for subsequent lysosomal hydrolysis.…”

Section: Alternative Functions Of Autophagy Machinery In Lipid Metabomentioning

confidence: 99%

Classical and alternative roles for autophagy in lipid metabolism

Zhang

Evans

Jeong

et al. 2018

Current Opinion in Lipidology

View full text Add to dashboard Cite

Purpose of review Intracellular lipid metabolism is a complex interplay of exogenous lipid handling, trafficking, storage, lipolysis, and export. Recent work has implicated the cellular degradative process called autophagy in several aspects of lipid metabolism. We will discuss both the classical and novel roles of autophagy and the autophagic machinery in this setting. Recent findings The delivery of lipid droplets to lysosomes for hydrolysis, named lipophagy, was the first described functional role for autophagy in lipid metabolism. The molecular machinery and regulation of this selective form of macroautophagy is beginning to be discovered and has the potential to shed enormous light on intracellular lipolysis. Yet, the autophagic machinery appears to also be coopted for alternative roles that include interaction with cytosolic lipolysis pathways, supply and expansion of lipid droplets, and lipoprotein trafficking. Additionally, lesser studied forms of autophagy called microautophagy and chaperone-mediated autophagy have distinct roles in lipid handling that also intersect with classical macroautophagy. The integration of current knowledge in these areas into a holistic understanding of intracellular lipid metabolism will be a goal of this review. Summary As the field of autophagy has evolved and expanded to include functional roles in various aspects of cellular degradation, so has its role in intracellular lipid metabolism. Understanding the mechanisms underlying these classical and alternative roles of autophagy will not only enhance our knowledge in lipid biology but also provide new avenues of translation to human lipid disorders.

show abstract

Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100

Abstract: These results strongly suggest that an unconventional lysosomal targeting process dependent on autophagy degrades apoB that was diverted from the secretory pathway by sortilin and provides a mechanism contributing to the reduced LDL-C found in individuals with overexpression.

Cited by 39 publications

References 58 publications

Hsp104 facilitates the endoplasmic‐reticulum–associated degradation of disease‐associated and aggregation‐prone substrates

Hsp104 facilitates the endoplasmic‐reticulum–associated degradation of disease‐associated and aggregation‐prone substrates

β-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice

Classical and alternative roles for autophagy in lipid metabolism

Contact Info

Product

Resources

About