Proteolytic enzymes belonging to the A Disintegin And Metalloproteinase (ADAM) family are able to cleave transmembrane proteins close to the cell surface, in a process referred to as ectodomain ...shedding. Substrates for ADAMs include growth factors, cytokines, chemokines and adhesion molecules, and, as such, many ADAM proteins play crucial roles in cell-cell adhesion, extracellular and intracellular signaling, cell differentiation and cell proliferation. In this Review, we summarize the fascinating roles of ADAMs in embryonic and adult tissue development in both vertebrates and invertebrates.
There is an exciting increase of evidence that members of the disintegrin and metalloprotease (ADAM) family critically regulate cell adhesion, migration, development and signalling. ADAMs are ...involved in “ectodomain shedding” of various cell surface proteins such as growth factors, receptors and their ligands, cytokines, and cell adhesion molecules. The regulation of these proteases is complex and still poorly understood. Studies in ADAM knockout mice revealed their partially redundant roles in angiogenesis, neurogenesis, tissue development and cancer. ADAMs usually trigger the first step in regulated intramembrane proteolysis leading to activation of intracellular signalling pathways and the release of functional soluble ectodomains.
The role of mutations in the gene GBA1 encoding the lysosomal hydrolase β‐glucocerebrosidase for the development of synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, was ...only very recently uncovered. The knowledge obtained from the study of carriers or patients suffering from Gaucher disease (a common lysosomal storage disorder because of GBA1 mutations) is of particular importance for understanding the role of the enzyme and its catabolic pathway in the development of synucleinopathies. Decreased activity of β‐glucocerebrosidase leads to lysosomal dysfunction and the accumulation of its substrate glucosylceramide and related lipid derivatives. Glucosylceramide is suggested to stabilize toxic oligomeric forms of α‐synuclein that negatively influence the activity of β‐glucocerebrosidase and to partially block export of newly synthesized β‐glucocerebrosidase from the endoplasmic reticulum to late endocytic compartments, amplifying the pathological effects of α‐synuclein and ultimately resulting in neuronal cell death. This pathogenic molecular feedback loop and most likely other factors (such as impaired endoplasmic reticulum‐associated degradation, activation of the unfolded protein response and dysregulation of calcium homeostasis induced by misfolded GC mutants) are involved in shifting the cellular homeostasis from monomeric α‐synuclein towards oligomeric neurotoxic and aggregated forms, which contribute to Parkinson's disease progression. From a therapeutic point of view, strategies aiming to increase either the expression, stability or delivery of the β‐glucocerebrosidase to lysosomes are likely to decrease the α‐synuclein burden and may be useful for an in depth evaluation at the organismal level.
Lysosomes are critical for protein and lipid homeostasis. Recent research revealed that dysfunction of this organelle contributes to the development of neurodegenerative diseases such as Parkinson's disease (PD). Mutations in the lysosomal hydrolase β‐glucocerebrosidase (GBA1) are a major risk factor for the development of PD and the molecular events linked to the reduced activity of GBA1 and the pathological accumulation of lipids and α‐synuclein are just at the beginning to be understood. New therapeutic concepts in regards to how to increase the expression, stability, or delivery of β‐glucocerebrosidase to lysosomes are currently developed.
This article is part of a special issue on Parkinson disease.
Lysosomes are critical for protein and lipid homeostasis. Recent research revealed that dysfunction of this organelle contributes to the development of neurodegenerative diseases such as Parkinson's disease (PD). Mutations in the lysosomal hydrolase β‐glucocerebrosidase (GBA1) are a major risk factor for the development of PD and the molecular events linked to the reduced activity of GBA1 and the pathological accumulation of lipids and α‐synuclein are just at the beginning to be understood. New therapeutic concepts in regards to how to increase the expression, stability, or delivery of β‐glucocerebrosidase to lysosomes are currently developed.
This article is part of a special issue on Parkinson disease.
Loss of function mutations in progranulin (GRN) cause frontotemporal dementia, but how GRN haploinsufficiency causes neuronal dysfunction remains unclear. We previously showed that GRN is ...neurotrophic in vitro. Here, we used an in vivo axonal outgrowth system and observed a delayed recovery in GRN-/- mice after facial nerve injury. This deficit was rescued by reintroduction of human GRN and relied on its C-terminus and on neuronal GRN production. Transcriptome analysis of the facial motor nucleus post injury identified cathepsin D (CTSD) as the most upregulated gene. In aged GRN-/- cortices, CTSD was also upregulated, but the relative CTSD activity was reduced and improved upon exogenous GRN addition. Moreover, GRN and its C-terminal granulin domain granulinE (GrnE) both stimulated the proteolytic activity of CTSD in vitro. Pull-down experiments confirmed a direct interaction between GRN and CTSD. This interaction was also observed with GrnE and stabilized the CTSD enzyme at different temperatures. Investigating the importance of this interaction for axonal regeneration in vivo we found that, although individually tolerated, a combined reduction of GRN and CTSD synergistically reduced axonal outgrowth. Our data links the neurotrophic effect of GRN and GrnE with a lysosomal chaperone function on CTSD to maintain its proteolytic capacity.
Cargo sorting to intraluminal vesicles (ILVs) of multivesicular endosomes is required for lysosome-related organelle (LRO) biogenesis. PMEL—a component of melanocyte LROs (melanosomes)—is sorted to ...ILVs in an ESCRT-independent manner, where it is proteolytically processed and assembled into functional amyloid fibrils during melanosome maturation. Here we show that the tetraspanin CD63 directly participates in ESCRT-independent sorting of the PMEL luminal domain, but not of traditional ESCRT-dependent cargoes, to ILVs. Inactivating CD63 in cell culture or in mice impairs amyloidogenesis and downstream melanosome morphogenesis. Whereas CD63 is required for normal PMEL luminal domain sorting, the disposal of the remaining PMEL transmembrane fragment requires functional ESCRTs but not CD63. In the absence of CD63, the PMEL luminal domain follows this fragment and is targeted for ESCRT-dependent degradation. Our data thus reveal a tight interplay regulated by CD63 between two distinct endosomal ILV sorting processes for a single cargo during LRO biogenesis.
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► ESCRT-independent sorting of PMEL to intraluminal vesicles depends on CD63 ► CD63 depletion inhibits formation of PMEL-derived amyloid fibers in vitro and in vivo ► PMEL C-terminal fragment is degraded in an ESCRT-dependent manner ► PMEL becomes sensitive to ESCRT-dependent degradation in CD63-depleted cells
Emerging concepts suggest that the functional phenotype of macrophages is regulated by transcription factors that define alternative activation states. We found that RBP-J, the main nuclear ...transducer of signaling via Notch receptors, augmented Toll-like receptor 4 (TLR4)-induced expression of key mediators of classically activated M1 macrophages and thus of innate immune responses to Listeria monocytogenes. Notch-RBP-J signaling controlled expression of the transcription factor IRF8 that induced downstream M1 macrophage-associated genes. RBP-J promoted the synthesis of IRF8 protein by selectively augmenting kinase IRAK2-dependent signaling via TLR4 to the kinase MNK1 and downstream translation-initiation control through eIF4E. Our results define a signaling network in which signaling via Notch-RBP-J and TLRs is integrated at the level of synthesis of IRF8 protein and identify a mechanism by which heterologous signaling pathways can regulate the TLR-induced inflammatory polarization of macrophages.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tetraspanins are a family of ubiquitously expressed and conserved proteins, which are characterized by four transmembrane domains and the formation of a short and a large extracellular loop (LEL). ...Through interaction with other tetraspanins and transmembrane proteins such as growth factors, receptors and integrins, tetraspanins build a wide ranging and membrane spanning protein network. Such tetraspanin-enriched microdomains (TEMs) contribute to the formation and stability of functional signaling complexes involved in cell activation, adhesion, motility, differentiation, and malignancy. There is increasing evidence showing that the tetraspanins also regulate the proteolysis of the amyloid precursor protein (APP) by physically interacting with the APP secretases. CD9, CD63, CD81, Tspan12, Tspan15 are among the tetraspanins involved in the intracellular transport and in the stabilization of the gamma secretase complex or ADAM10 as the major APP alpha secretase. They also directly regulate, most likely in concert with other tetraspanins, the proteolytic function of these membrane embedded enzymes. Despite the knowledge about the interaction of tetraspanins with the secretases not much is known about their physiological role, their importance in Alzheimer's Disease and their exact mode of action. This review aims to summarize the current knowledge and open questions regarding the biology of tetraspanins and the understanding how these proteins interact with APP processing pathways. Ultimately, it will be of interest if tetraspanins are suitable targets for future therapeutical approaches.
Lysosomes are in the center of the cellular control of catabolic and anabolic processes. These membrane-surrounded acidic organelles contain around 70 hydrolases, 200 membrane proteins, and numerous ...accessory proteins associated with the cytosolic surface of lysosomes. Accessory and transmembrane proteins assemble in signaling complexes that sense and integrate multiple signals and transmit the information to the nucleus. This communication allows cells to respond to changes in multiple environmental conditions, including nutrient levels, pathogens, energy availability, and lysosomal damage, with the goal of restoring cellular homeostasis. This review summarizes our current understanding of the major molecular players and known pathways that are involved in control of metabolic and stress responses that either originate from lysosomes or regulate lysosomal functions.
Lysosomes are key sensors and mediators to quickly adapt cellular metabolism to environmental changes. They collect information about changing environmental conditions, translating it into cellular adaptations.Mechanistic target of rapamycin complex 1 (mTORC1) is activated on lysosomes by growth factors and amino acids, promoting many anabolic processes and inhibiting autophagy. The lysosomal membrane proteins v-ATPase and SLC38A9 sense intraluminal amino acids and transmit signals to the Ragulator complex.Lysosomes act as platforms for AMP-activated protein kinase (AMPK) activation, glucose sensing, and regulation of the cellular response after glucose deprivation and energy stress. AMPK activation promotes catabolic processes.Cholesterol in lysosomal membranes interacts with the mTORC1 machinery and promotes Rag-GTPase-mediated mTORC1 activation. Also, phosphoinositides impact lysosome function and modulate nutrient signaling.Some Toll-like receptors sense intraluminal nucleic acids in lysosomes and regulate immune responses. They are also involved in crossregulation between immune and metabolic sensors controlling mTORC1.Damaged lysosomes are repaired or removed by mechanisms involving the endosomal sorting complex required for transport (ESCRT) complex machinery, or recognition by galectins leading to autophagy activation, respectively.The MiT/TFE transcription factor family members can be activated by changes in environmental conditions, thereby regulating stress response pathways and contributing to the restoration of cellular homeostasis.Oxidative stress inside lysosomes, as observed in lysosomal-mediated cell death and cancer, activates signal transducer and activator of transcription-3 (STAT3), triggering the expression of multiple lysosomal hydrolases.The forkhead box O (FoxO) family of transcription factors controls autophagy by causing increased transcription of autophagy genes after promoter binding, induction of epigenetic changes, and interaction with autophagy proteins.MYC and zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) transcription factors antagonize MiT/TFE transcription factors and repress autophagy and lysosomal biogenesis.
The intracellular transport of cholesterol is subject to tight regulation. The structure of the lysosomal integral membrane protein type 2 (LIMP-2, also known as SCARB2) reveals a large cavity that ...traverses the molecule and resembles the cavity in SR-B1 that mediates lipid transfer. The detection of cholesterol within the LIMP-2 structure and the formation of cholesterol
like inclusions in LIMP-2 knockout mice suggested the possibility that LIMP2 transports cholesterol in lysosomes. We present results of molecular modeling, crosslinking studies, microscale thermophoresis and cell-based assays that support a role of LIMP-2 in cholesterol transport. We show that the cavity in the luminal domain of LIMP-2 can bind and deliver exogenous cholesterol to the lysosomal membrane and later to lipid droplets. Depletion of LIMP-2 alters SREBP-2-mediated cholesterol regulation, as well as LDL-receptor levels. Our data indicate that LIMP-2 operates in parallel with Niemann Pick (NPC)-proteins, mediating a slower mode of lysosomal cholesterol export.
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