PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing

Gavin, Amanda L.; Huang, Deli; Huber, Christoph; Mårtensson, Annica; Tardif, Virginie; Skog, Patrick; Blane, Tanya R.; Thinnes, Terri; Osborn, Kent G.; Chong, Hayley S.; Kargaran, Farnaz; Kimm, Phoebe; Zeitjian, Armen; Sielski, Rachel L.; Briggs, Megan; Schulz, Sebastian; Zarpellon, Alessandro; Cravatt, Benjamin F.; Pang, Ee Shan; Teijaro, John R.; Torre, Juan Carlos de la; O’Keeffe, Meredith; Hochrein, Hubertus; Damme, Markus; Teyton, Luc; Lawson, Brian R.; Nemazee, David

doi:10.1038/s41590-018-0179-y

Cited by 108 publications

(143 citation statements)

References 57 publications

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“…Unique SARS-CoV-2 interactors include FOXK1 and NR2F2, both of which are anti-viral transcription factors induced in response to other viruses 27,28 . We also observe an exonuclease regulator of endosomal nucleic acid sensing (PLD3) 29 , a transcription factor associated with the influenza humoral response (MAZ) 30,31 , and a DNA-binding protein implicated in B cell class switching (KIN or KIN17) 32 . In contrast, the list of unique SARS-CoV-1 interactors includes components of the 4EFP-GYF2 translation repression complex (GYGYF2, EIF4E2), lysosomal ion channels involved in chloride/proton ion exchange (CLCN7, OSTM1), and the cytosolic histone deacetylase 6 (HDAC6).…”

Section: Quantitative Comparison Of Sars-cov-1 and Sars-cov-2 Interacmentioning

confidence: 93%

Comparative multiplexed interactomics of SARS-CoV-2 and homologous coronavirus non-structural proteins identifies unique and shared host-cell dependencies

Davies

Almasy

McDonald

et al. 2020

Preprint

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Human coronaviruses (hCoV) have become a threat to global health and society, as evident from the SARS outbreak in 2002 caused by SARS-CoV-1 and the most recent COVID-19 pandemic caused by SARS-CoV-2. Despite high sequence similarity between SARS-CoV-1 and -2, each strain has distinctive virulence. A better understanding of the basic molecular mechanisms mediating changes in virulence is needed. Here, we profile the virus-host protein-protein interactions of two hCoV non-structural proteins (nsps) that are critical for virus replication. We use tandem mass tag-multiplexed quantitative proteomics to sensitively compare and contrast the interactomes of nsp2 and nsp4 from three betacoronavirus strains: SARS-CoV-1, SARS-CoV-2, and hCoV-OC43 - an endemic strain associated with the common cold. This approach enables the identification of both unique and shared host cell protein binding partners and the ability to further compare the enrichment of common interactions across homologs from related strains. We identify common nsp2 interactors involved in endoplasmic reticulum (ER) Ca2+ signaling and mitochondria biogenesis. We also identifiy nsp4 interactors unique to each strain, such as E3 ubiquitin ligase complexes for SARS-CoV-1 and ER homeostasis factors for SARS-CoV-2. Common nsp4 interactors include N-linked glycosylation machinery, unfolded protein response (UPR) associated proteins, and anti-viral innate immune signaling factors. Both nsp2 and nsp4 interactors are strongly enriched in proteins localized at mitochondrial-associated ER membranes suggesting a new functional role for modulating host processes, such as calcium homeostasis, at these organelle contact sites. Our results shed light on the role these hCoV proteins play in the infection cycle, as well as host factors that may mediate the divergent pathogenesis of OC43 from SARS strains. Our mass spectrometry workflow enables rapid and robust comparisons of multiple bait proteins, which can be applied to additional viral proteins. Furthermore, the identified common interactions may present new targets for exploration by host-directed anti-viral therapeutics.

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Section: Quantitative Comparison Of Sars-cov-1 and Sars-cov-2 Interacmentioning

confidence: 93%

Comparative multiplexed interactomics of SARS-CoV-2 and homologous coronavirus non-structural proteins identifies unique and shared host-cell dependencies

Davies

Almasy

McDonald

et al. 2020

Preprint

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“…There are a few non-canonical functions of PLDs which include nuclease activity and cardiolipase activity, both of which are mediated by substrate binding at the HKD motif 3,4 . Phospholipase D1 and D2 (PLD1 and PLD2), are confirmed to be enzymatically active mammalian PLD isoforms and are druggable proteins 2,5 .…”

Section: Introductionmentioning

confidence: 99%

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease

Nackenoff

Hohman

Neuner

et al. 2019

Preprint

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PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease ABSTRACT Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer's disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to determine whether PLD3 is relevant to memory and cognition in sporadic AD, to observe its distribution in normal human brain and AD-affected brain, to describe its subcellular localization, and to evaluate its molecular function. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both βamyloid pathology and cognition.

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“…Spleen samples were prepared as previously described (62). In brief, spleen suspensions were generated by smashing the spleen between frosted glass slides.…”

Section: Flow Cytometry Analysismentioning

confidence: 99%

B cells expressing authentic naive human VRC01-class BCRs can be primed and recruited to germinal centers in multiple independent mouse models

Huang

Abbott

Havenar-Daughton

et al. 2020

Preprint

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Animal models of human antigen-specific B cell receptors (BCR) generally depend on "inferred germline" sequences, and thus their relationship to authentic naive human B cell BCR sequences and affinities is unclear. Here, BCR sequences from authentic naive human VRC01-class B cells from healthy human donors were selected for the generation of three new BCR knock-in mice.The BCRs span the physiological range of affinities found in humans, and use three different light chains (VK3-20, VK1-5, and VK1-33) found among subclasses of naive human VRC01-class B cells and HIV broadly neutralizing antibodies (bnAbs). The germline-targeting HIV immunogen eOD-GT8 60mer is currently in clinical trial as a candidate bnAb vaccine priming immunogen. To attempt to model human immune responses to the eOD-GT8 60mer, we tested each authentic naive human VRC01-class BCR mouse model under rare human physiological B cell precursor frequency conditions. B cells with high (HuGL18 HL ) or medium (HuGL17 HL ) affinity BCRs were primed, recruited to germinal centers, accrued substantial somatic hypermutation, and formed memory B cells. Precursor frequency and affinity interdependently influenced responses. Taken together, these experiments utilizing authentic naive human VRC01-class BCRs validate a central tenet of germline-targeting vaccine design and extend the overall concept of the reverse vaccinology approach to vaccine development.

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PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing

Cited by 108 publications

References 57 publications

Comparative multiplexed interactomics of SARS-CoV-2 and homologous coronavirus non-structural proteins identifies unique and shared host-cell dependencies

Comparative multiplexed interactomics of SARS-CoV-2 and homologous coronavirus non-structural proteins identifies unique and shared host-cell dependencies

PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease

B cells expressing authentic naive human VRC01-class BCRs can be primed and recruited to germinal centers in multiple independent mouse models

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