It Takes Two to Tango: Activation of Protein Kinase D by Dimerization

Reinhardt, Ronja; Truebestein, Linda; Schmidt, Heiko A.; Leonard, Thomas A.

doi:10.1002/bies.201900222

Cited by 17 publications

(12 citation statements)

References 115 publications

(260 reference statements)

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“…Second, the importance of PKD enzymes for trafficking from the trans-Golgi network, a cellular compartment, which, upon treatment with NLRP3 activators becomes closely associated with mitochondria-associated endoplasmic reticulum membranes where NLRP3 is located (11). Third, the recent evidence for PKD dimerization and activation, which may take place at various subcellular locations including the trans-Golgi network (28), where diacylglycerol is known to be produced upon NLRP3 activation (11).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of protein kinase D auto-phosphorylation as biomarker for NLRP3 inflammasome activation

Heiser¹,

Rubert²,

Unterreiner³

et al. 2021

Preprint

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The NLRP3 inflammasome is a critical component of sterile inflammation, which is involved in many diseases. However, there is currently no known proximal biomarker for measuring NLRP3 activation in pathological conditions. Protein kinase D (PKD) has emerged as an important NLRP3 kinase that catalyzes the release of a phosphorylated NLRP3 species that is competent for inflammasome complex assembly. To explore the potential for PKD activation to serve as a selective biomarker of the NLRP3 pathway, we tested various stimulatory conditions in THP-1 and U937 cell lines, probing the inflammasome space beyond NLRP3. We analyzed the correlation between PKD activation (monitored by its auto-phosphorylation) and functional inflammasome readouts. PKD activation/auto-phosphorylation always preceded cleavage of caspase-1 and gasdermin D, and treatment with the PKD inhibitor CRT0066101 could block NLRP3 inflammasome assembly and interleukin-1β production. Conversely, blocking NLRP3 either genetically or using the MCC950 inhibitor prevented PKD auto-phosphorylation, indicating a bidirectional functional crosstalk between NLRP3 and PKD. Further assessments of the pyrin and NLRC4 pathways, however, revealed that PKD auto-phosphorylation can be triggered by a broad range of stimuli unrelated to NLRP3 inflammasome assembly. Thus, although PKD and NLRP3 become functionally interconnected during NLRP3 activation, the promiscuous reactivity of PKD challenges its potential use for tracing the NLRP3 inflammasome pathway.

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Section: Discussionmentioning

confidence: 99%

Evaluation of protein kinase D auto-phosphorylation as biomarker for NLRP3 inflammasome activation

Heiser¹,

Rubert²,

Unterreiner³

et al. 2021

Preprint

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show abstract

“…PKD is a family of serine/threonine-protein kinases that, in humans, encompasses 3 canonical members: PKD1 (also known as PKCµ; gene name PRKD1 ), PKD2 (gene name PRKD2 ), and PKD3 (also known as PKCν; gene name PRKD3 ) [ 31 , 58 ]. Although no PKD ortholog has been described in yeast, PKD family members are conserved throughout evolution from nematodes to humans [ 59 ]. PKD plays different functions in cell physiology [ 58 ], such as (i) promoting export from the TGN by assisting in the membrane fission reaction [ 17 , 25 , 26 , 30 , 31 , 58 ]; (ii) mediating cell migration by controlling integrin recycling and recruitment in focal adhesions [ 28 , 52 ]; (iii) contributing to cell survival under oxidative stress [ 60 ]; and (iv) activating inflammasomes to initiate the innate immune response [ 61 ].…”

Section: Pkd Is a Key Regulator Of Tgn Export And Golgi Lipid Homeostasismentioning

confidence: 99%

“…At the N terminus, PKD1 and PKD2, but not PKD3, contain a short amino acid stretch rich in prolines and alanines, which is postulated to act as a membrane insertion domain [ 31 , 69 ]. PKD also contains a ubiquitin-like domain (ULD) that allows for homo- and hetero-dimerization [ 27 , 59 , 70 , 71 ]. Next, as part of its N-terminal regulatory domain, PKD contains a pair of cysteine-rich domains, termed C1a and C1b, respectively.…”

Section: Pkd Is a Key Regulator Of Tgn Export And Golgi Lipid Homeostasismentioning

confidence: 99%

The PKD-Dependent Biogenesis of TGN-to-Plasma Membrane Transport Carriers

Wakana

Campelo

2021

Cells

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Membrane trafficking is essential for processing and transport of proteins and lipids and to establish cell compartmentation and tissue organization. Cells respond to their needs and control the quantity and quality of protein secretion accordingly. In this review, we focus on a particular membrane trafficking route from the trans-Golgi network (TGN) to the cell surface: protein kinase D (PKD)-dependent pathway for constitutive secretion mediated by carriers of the TGN to the cell surface (CARTS). Recent findings highlight the importance of lipid signaling by organelle membrane contact sites (MCSs) in this pathway. Finally, we discuss our current understanding of multiple signaling pathways for membrane trafficking regulation mediated by PKD, G protein-coupled receptors (GPCRs), growth factors, metabolites, and mechanosensors.

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“…Upon activation, they control different intracellular processes such as vesicle fission from the Golgi complex and rearrangement of the actin cytoskeleton (reviewed in (Olayioye et al . 2013; Reinhardt et al . 2020)).…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase D promotes activity-dependent AMPA receptor endocytosis in hippocampal neurons

Morales

Ignácz

Bencsik

et al. 2020

Preprint

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AMPA type glutamate receptors (AMPARs) mediate the majority of fast excitatory neurotransmission in the brain. The continuous trafficking of AMPARs into and out of synapses is a core feature of synaptic plasticity, which is considered as the cellular basis of learning and memory. The molecular mechanisms underlying the postsynaptic AMPAR trafficking, however, are still not fully understood. In this work, we demonstrate that the Protein Kinase D (PKD) family promotes basal and activity-induced AMPAR endocytosis in primary hippocampal neurons. Pharmacological inhibition of PKD increased synaptic levels of GluA1containing AMPARs and slowed down their endocytic trafficking. By contrast, ectopic expression of constitutive active PKD decreased the synaptic level of AMPARs, while increasing their co-localization with early endosomes. On a molecular level, we identify PKDmediated phosphorylation of the Rab5 effector protein Rabaptin-5 to be required for promoting activity-dependent AMPAR endocytosis. Our results thus establish an important role for PKD in the regulation of postsynaptic AMPAR trafficking during synaptic plasticity.

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It Takes Two to Tango: Activation of Protein Kinase D by Dimerization

Cited by 17 publications

References 115 publications

Evaluation of protein kinase D auto-phosphorylation as biomarker for NLRP3 inflammasome activation

Evaluation of protein kinase D auto-phosphorylation as biomarker for NLRP3 inflammasome activation

The PKD-Dependent Biogenesis of TGN-to-Plasma Membrane Transport Carriers

Protein Kinase D promotes activity-dependent AMPA receptor endocytosis in hippocampal neurons

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