Microautophagy of Cytosolic Proteins by Late Endosomes

Sahu, Ranjit; Kaushik, Susmita; Clement, Cristina C.; Cannizzo, Elvira S.; Scharf, Brian; Follenzi, Antonia; Potolicchio, Ilaria; Nieves, Edward; Cuervo, Ana María; Santambrogio, Laura

doi:10.1016/j.devcel.2011.02.011

Cited by 78 publications

(133 citation statements)

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“…This engulfment of cytosolic proteins results of a microautophagy process [22], and appears to involve proteins located close to the MVB outer membrane during its inward budding, which could explain the presence of mRNAs and miRNAs in exosomes [23]. In that respect two major components of the RNA-Induced Silencing Complex (RISC) have been shown to associate with MVB and to be sorted into exosomes [24].…”

Section: Incorporation Of Cytosolic Proteins Into Exosomesmentioning

confidence: 99%

“…AEBS is a molecular complex constituted by two cholesterogenic enzymes, the DHCR7 reductase and the D8D7I isomerase, whose association makes a third catalytic activity, namely the cholesterol epoxyde hydrolase [32]. Ligands of AEBS trigger macroautophagy in tumor cells through modulation of cholesterol metabolism [33],and a link between microautophagy of the late endosome compartment and exosome 6 production has been proposed [22], suggesting a role of cholesterol in exosome biogenesis. Noteworthy, the ATPase Vps4 which binds ECRTIII in the ESCRT machinery (see § 1.1) also interacts with oxysterol binding proteins and sterol metabolism [34].…”

Section: Sorting Lipids In Exosomes (Figure 2)mentioning

confidence: 99%

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Exosomes as intercellular signalosomes and pharmacological effectors

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Silvente-Poirot

et al. 2011

Biochemical Pharmacology

481

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International audienceCell secretion is a general process involved in various biological responses. Exosomes are part of this process and have gained considerable scientific interest in the past five years. Several steps through investigations across the last 20years can explain this interest. First characterized during reticulocyte maturation, they were next characterized as a key player in the immune response and cancer immunotherapy. More recently they were characterized as vectors of mRNAs, miRNAs and also lipid mediators able to act on target cells. They are the only type of vesicles released from an intracellular compartment from cells in viable conditions. They appear as a vectorized signaling system operating from inside a donor cell towards either the periphery, the cytosol, or possibly to the nucleus of target cells. Exosomes from normal cells trigger positive effects, whereas those from pathological ones, such as tumor cells or infected ones may trigger non-positive health effects. Therefore regulating the biogenesis and secretion of exosomes appear as a pharmacological challenge to intervene in various pathophysiologies. Exosome biogenesis and molecular content, interaction with target cells, utilisation as biomarkers, and functional effects in various pathophysiologies are considered in this review

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Section: Incorporation Of Cytosolic Proteins Into Exosomesmentioning

confidence: 99%

Section: Sorting Lipids In Exosomes (Figure 2)mentioning

confidence: 99%

Exosomes as intercellular signalosomes and pharmacological effectors

Record

Subra

Silvente-Poirot

et al. 2011

Biochemical Pharmacology

481

336

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“…Validation of a protein as a CMA substrate requires more than the mere identification of a putative CMA targeting motif in its amino acid sequence, as this motif has also been recently shown to be utilized for targeting of proteins to late endosomes for endosomal microautophagy [32]. Although both CMA and endosomal microautophagy share hsc70 as the targeting chaperone, the dependence on LAMP-2A is exclusive for CMA.…”

Section: How Does Cma Work?mentioning

confidence: 99%

Chaperone-mediated autophagy: roles in disease and aging

2013

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This review focuses on chaperone-mediated autophagy (CMA), one of the proteolytic systems that contributes to degradation of intracellular proteins in lysosomes. CMA substrate proteins are selectively targeted to lysosomes and translocated into the lysosomal lumen through the coordinated action of chaperones located at both sides of the membrane and a dedicated protein translocation complex. The selectivity of CMA permits timed degradation of specific proteins with regulatory purposes supporting a modulatory role for CMA in enzymatic metabolic processes and subsets of the cellular transcriptional program. In addition, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. Here, we describe recent advances in the understanding of the molecular dynamics, regulation and physiology of CMA, and discuss the evidence in support of the contribution of CMA dysfunction to severe human disorders such as neurodegeneration and cancer.

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“…These processes include among others activation of the immune system (De Maio 2011, 2014Gehrmann et al 2004;Henderson 2010;Multhoff and Hightower 1996;Vega et al 2008), cytoprotection of injured neural and other cells, suppression of tumor growth (Brown 2007;Chen et al 2005;Gehrmann et al 2008;Henderson 2010;Lancaster et al 2004;Schmitt et al 2007;Tytell 2005), channel formation (Arispe and De Maio 2000;Arispe et al 2004), and promotion of apoptosis (Broquet et al 2003;Gastpar et al 2005;Gehrmann et al 2008;Multhoff and Hightower 1996;Schilling et al 2009). Intracellularly, Hsp70s' interaction with lipids prevents cell death by stabilizing the lysosomal membrane , regulates cell survival by mediating microautophagy (Sahu et al 2011), and acts as cytosolic carrier of the endogenous cannabinoid lipid anandamide (Oddi et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Biochemical characterization of the interaction between HspA1A and phospholipids

McCallister¹,

Kdeiss²,

Nikolaidis³

2016

Cell Stress and Chaperones

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Seventy-kilodalton heat shock proteins (Hsp70s) are molecular chaperones essential for maintaining cellular homeostasis. Apart from their indispensable roles in protein homeostasis, specific Hsp70s localize at the plasma membrane and bind to specific lipids. The interaction of Hsp70s with lipids has direct physiological outcomes including lysosomal rescue, microautophagy, and promotion of cell apoptosis. Despite these essential functions, the Hsp70-lipid interactions remain largely uncharacterized. In this study, we characterized the interaction of HspA1A, an inducible Hsp70, with five phospholipids. We first used high concentrations of potassium and established that HspA1A embeds in membranes when bound to all anionic lipids tested. Furthermore, we found that protein insertion is enhanced by increasing the saturation level of the lipids. Next, we determined that the nucleotide-binding domain (NBD) of the protein binds to lipids quantitatively more than the substrate-binding domain (SBD). However, for all lipids tested, the full-length protein is necessary for embedding. We also used calcium and reaction buffers equilibrated at different pH values and determined that electrostatic interactions alone may not fully explain the association of HspA1A with lipids. We then determined that lipid binding is inhibited by nucleotide-binding, but it is unaffected by protein-substrate binding. These results suggest that the HspA1A lipid-association is specific, depends on the physicochemical properties of the lipid, and is mediated by multiple molecular forces. These mechanistic details of the Hsp70-lipid interactions establish a framework of possible physiological functions as they relate to chaperone regulation and localization.

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Microautophagy of Cytosolic Proteins by Late Endosomes

Cited by 78 publications

References 0 publications

Exosomes as intercellular signalosomes and pharmacological effectors

Exosomes as intercellular signalosomes and pharmacological effectors

Chaperone-mediated autophagy: roles in disease and aging

Biochemical characterization of the interaction between HspA1A and phospholipids

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