Stress granules (SGs) are mRNA-protein aggregates induced during stress, which accumulate in many... more Stress granules (SGs) are mRNA-protein aggregates induced during stress, which accumulate in many neurodegenerative diseases. Previously, the autophagy-lysosome pathway and valosin-containing protein (VCP), key players of the protein quality control (PQC), were shown to regulate SG degradation. This is consistent with the idea that PQC may survey and/or assist SG dynamics. However, despite these observations, it is currently unknown whether the PQC actively participates in SG assembly. Here, we describe that inhibition of autophagy, lysosomes and VCP causes defective SG formation after induction. Silencing the VCP co-factors UFD1L and PLAA, which degrade defective ribosomal products (DRIPs) and 60S ribosomes, also impaired SG assembly. Intriguingly, DRIPs and 60S, which are released from disassembling polysomes and are normally excluded from SGs, were significantly retained within SGs in cells with impaired autophagy, lysosome or VCP function. Our results suggest that deregulated au...
Eukaryotic cells use autophagy and the ubiquitin-proteasome system as their major protein degrada... more Eukaryotic cells use autophagy and the ubiquitin-proteasome system as their major protein degradation pathways. Upon proteasomal impairment, cells switch to autophagy to ensure proper clearance of clients (the proteasome-to-autophagy switch). The HSPA8 and HSPA1A cochaperone BAG3 has been suggested to be involved in this switch. However, at present it is still unknown whether and to what extent BAG3 can indeed reroute proteasomal clients to the autophagosomal pathway. Here, we show that BAG3 induces the sequestration of ubiquitinated clients into cytoplasmic puncta colabeled with canonical autophagy linkers and markers. Following proteasome inhibition, BAG3 upregulation significantly contributes to the compensatory activation of autophagy and to the degradation of the (poly)ubiquitinated proteins. BAG3 binding to the ubiquitinated clients occurs through the BAG domain, in competition with BAG1, another BAG family member, that normally directs ubiquitinated clients to the proteasome....
We recently reported the existence of medium and large intemeurons immunoreactive for the calcium... more We recently reported the existence of medium and large intemeurons immunoreactive for the calcium-binding protein calretinin in the human striatum. We also showed a selective sparing of all medium, but not all large, calretinin-immunoreactive striatal neurons in Huntington's disease striatum. Because glutamate receptor-mediated excitotoxicity has been implicated in the massive loss of striatal projection neurons that characterizes Huntington's disease, we have applied a double-antigen localization procedure to post mortem tissue from eight normal human subjects to determine the expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor subunits 1/2/4 by the calretinin-immunoreactive interneurons. The two types of calretinin-immunoreactive neurons were found to display various patterns of glutamate receptor subunit expression and a specific regionalization was also noted in the expression of these glutamate receptor subunits. Approximately half ...
Background and PurposeInduction of cellular migration is the primary effect of chemokine receptor... more Background and PurposeInduction of cellular migration is the primary effect of chemokine receptor activation. However, several chemokine receptor‐like proteins bind chemokines without subsequent induction of intracellular signalling and chemotaxis. It has been suggested that they act as chemokine scavengers, which may control local chemokine levels and contribute to the function of chemokines during inflammation. This has been verified for the chemokine‐like receptor proteins D6 and DARC as well as CCX‐CKR. Here, we provide evidence for an additional biological function of human (h)CCX‐CKR. Experimental ApproachWe used transfection strategies in HEK293 and human T cells. Key ResultsCo‐expression of hCCX‐CKR completely inhibits hCXCR3‐induced chemotaxis. We found that hCCX‐CKR forms complexes with hCXCR3, suggesting a relationship between CCX‐CKR heteromerization and inhibition of chemotaxis. Moreover, negative binding cooperativity induced by ligands both for hCXCR3 and hCCX‐CKR was...
The Ca2+/calmodulin-dependent protein kinase kinases alpha and beta (CaMKKs α and β) are novel me... more The Ca2+/calmodulin-dependent protein kinase kinases alpha and beta (CaMKKs α and β) are novel members of the CaM kinase family. The CaMKKβ was cloned from mouse brain. The deduced amino acid sequence shared 96.43% homology with the rat CaMKKβ. Both the α and β isoforms were widely distributed throughout the adult mouse brain. Additionally, all peripheral tissues examined displayed CaMKK
Stress granules (SGs) are mRNA-protein aggregates induced during stress, which accumulate in many... more Stress granules (SGs) are mRNA-protein aggregates induced during stress, which accumulate in many neurodegenerative diseases. Previously, the autophagy-lysosome pathway and valosin-containing protein (VCP), key players of the protein quality control (PQC), were shown to regulate SG degradation. This is consistent with the idea that PQC may survey and/or assist SG dynamics. However, despite these observations, it is currently unknown whether the PQC actively participates in SG assembly. Here, we describe that inhibition of autophagy, lysosomes and VCP causes defective SG formation after induction. Silencing the VCP co-factors UFD1L and PLAA, which degrade defective ribosomal products (DRIPs) and 60S ribosomes, also impaired SG assembly. Intriguingly, DRIPs and 60S, which are released from disassembling polysomes and are normally excluded from SGs, were significantly retained within SGs in cells with impaired autophagy, lysosome or VCP function. Our results suggest that deregulated au...
Eukaryotic cells use autophagy and the ubiquitin-proteasome system as their major protein degrada... more Eukaryotic cells use autophagy and the ubiquitin-proteasome system as their major protein degradation pathways. Upon proteasomal impairment, cells switch to autophagy to ensure proper clearance of clients (the proteasome-to-autophagy switch). The HSPA8 and HSPA1A cochaperone BAG3 has been suggested to be involved in this switch. However, at present it is still unknown whether and to what extent BAG3 can indeed reroute proteasomal clients to the autophagosomal pathway. Here, we show that BAG3 induces the sequestration of ubiquitinated clients into cytoplasmic puncta colabeled with canonical autophagy linkers and markers. Following proteasome inhibition, BAG3 upregulation significantly contributes to the compensatory activation of autophagy and to the degradation of the (poly)ubiquitinated proteins. BAG3 binding to the ubiquitinated clients occurs through the BAG domain, in competition with BAG1, another BAG family member, that normally directs ubiquitinated clients to the proteasome....
We recently reported the existence of medium and large intemeurons immunoreactive for the calcium... more We recently reported the existence of medium and large intemeurons immunoreactive for the calcium-binding protein calretinin in the human striatum. We also showed a selective sparing of all medium, but not all large, calretinin-immunoreactive striatal neurons in Huntington's disease striatum. Because glutamate receptor-mediated excitotoxicity has been implicated in the massive loss of striatal projection neurons that characterizes Huntington's disease, we have applied a double-antigen localization procedure to post mortem tissue from eight normal human subjects to determine the expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor subunits 1/2/4 by the calretinin-immunoreactive interneurons. The two types of calretinin-immunoreactive neurons were found to display various patterns of glutamate receptor subunit expression and a specific regionalization was also noted in the expression of these glutamate receptor subunits. Approximately half ...
Background and PurposeInduction of cellular migration is the primary effect of chemokine receptor... more Background and PurposeInduction of cellular migration is the primary effect of chemokine receptor activation. However, several chemokine receptor‐like proteins bind chemokines without subsequent induction of intracellular signalling and chemotaxis. It has been suggested that they act as chemokine scavengers, which may control local chemokine levels and contribute to the function of chemokines during inflammation. This has been verified for the chemokine‐like receptor proteins D6 and DARC as well as CCX‐CKR. Here, we provide evidence for an additional biological function of human (h)CCX‐CKR. Experimental ApproachWe used transfection strategies in HEK293 and human T cells. Key ResultsCo‐expression of hCCX‐CKR completely inhibits hCXCR3‐induced chemotaxis. We found that hCCX‐CKR forms complexes with hCXCR3, suggesting a relationship between CCX‐CKR heteromerization and inhibition of chemotaxis. Moreover, negative binding cooperativity induced by ligands both for hCXCR3 and hCCX‐CKR was...
The Ca2+/calmodulin-dependent protein kinase kinases alpha and beta (CaMKKs α and β) are novel me... more The Ca2+/calmodulin-dependent protein kinase kinases alpha and beta (CaMKKs α and β) are novel members of the CaM kinase family. The CaMKKβ was cloned from mouse brain. The deduced amino acid sequence shared 96.43% homology with the rat CaMKKβ. Both the α and β isoforms were widely distributed throughout the adult mouse brain. Additionally, all peripheral tissues examined displayed CaMKK
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Papers by Jonathan Vinet