ABHD16A Negatively Regulates the Palmitoylation and Antiviral Function of IFITM Proteins

Shi, Xuemeng; Li, Xiaoling; Shen, Lingyi; Ding, Yunyun; Chen, Shuaiwu; Lin, Min; Liu, Wei; Xu, Jun

doi:10.1128/mbio.02289-22

Cited by 9 publications

(11 citation statements)

References 58 publications

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“…ORF7A was only found to interact with the taste receptors TAS2R41 and TAS2R7, which is intriguing considering the genetic evidence of variant-of-concern-specific ORF7AB alleles in a hamster-model of anosmia [84] and TAS2R41 being identified as a potential host-factor in a loss-of-function screen in cellculture [85]. We confirmed the previous detection of ORF6 interacting with ABHD16A, a mechanism that may supplement ORF6's antagonism of cellular innate immunity [86][87][88][89]. NSP4 was found here to interact with KDEL-receptors (both KDELR2 and KDELR3), and this interaction with the ER-retention retrograde signaling pathway might shed light on the role this protein plays in shaping ER membrane into the double membrane vesicles important for viral replication [90][91][92].…”

Section: Ppiseq Complements Previous Human-sars-cov-2 Ppi Screenssupporting

confidence: 84%

Pooled PPIseq: screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform

Miller,

Dziulko,

Levy

2024

Preprint

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Protein-ProteinInteractions (PPIs) are a key interface between virus and host, and these interactions are important to both viral reprogramming of the host and to host restriction of viral infection. In particular, viral-host PPI networks can be used to further our understanding of the molecular mechanisms of tissue specificity, host range, and virulence. At higher scales, viral-host PPI screening could also be used to screen for small-molecule antivirals that interfere with essential viral-host interactions, or to explore how the PPI networks between interacting viral and host genomes co-evolve. Current high-throughput PPI assays have screened entire viral-host PPI networks. However, these studies are time consuming, often require specialized equipment, and are difficult to further scale. Here, we develop methods that make larger-scale viral-host PPI screening more accessible. This approach combines the mDHFR split-tag reporter with the iSeq2 interaction-barcoding system to permit massively-multiplexed PPI quantification by simple pooled engineering of barcoded constructs, integration of these constructs into budding yeast, and fitness measurements by pooled cell competitions and barcode-sequencing. We applied this method to screen for PPIs between SARS-CoV-2 proteins and human proteins, screening in triplicate >180,000 ORF-ORF combinations represented by >1,000,000 barcoded lineages. Our results complement previous screens by identifying 74 putative PPIs, including interactions between ORF7A with the taste receptors TAS2R41 and TAS2R7, and between NSP4 with the transmembrane KDELR2 and KDELR3. We show that this PPI screening method is highly scalable, enabling larger studies aimed at generating a broad understanding of how viral effector proteins converge on cellular targets to effect replication.

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Section: Ppiseq Complements Previous Human-sars-cov-2 Ppi Screenssupporting

confidence: 84%

Pooled PPIseq: screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform

Miller,

Dziulko,

Levy

2024

Preprint

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“…Through this mechanism, ABHD16A could promote membrane curvature for mitochondrial fission and fusion. Intriguingly, some ABHD family proteins are depalmitoylases, and new evidence suggests ABHD16A has the ability to depalmitoylate some transmembrane proteins ( Cao et al, 2019 ; Lin and Conibear, 2015 ; Shi et al, 2022 ). It is also plausible that ABHD16A could depalmitoylate some ER-mitochondria MCS proteins to alter their membrane affinity at nodes.…”

Section: Discussionmentioning

confidence: 99%

An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion

Nguyen

Voeltz

2022

eLife

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Mitochondria are dynamic organelles that undergo cycles of fission and fusion at a unified platform defined by endoplasmic reticulum (ER)-mitochondria membrane contact sites (MCSs). These MCSs or nodes co-localize fission and fusion machinery. We set out to identify how ER-associated mitochondrial nodes can regulate both fission and fusion machinery assembly. We have used a promiscuous biotin ligase linked to the fusion machinery, Mfn1, and proteomics to identify an ER membrane protein, ABHD16A, as a major regulator of node formation. In the absence of ABHD16A, fission and fusion machineries fail to recruit to ER-associated mitochondrial nodes and fission and fusion rates are significantly reduced. ABHD16A contains an acyltransferase motif and an α/β hydrolase domain and point mutations in critical residues of these regions fail to rescue the formation of ER-associated mitochondrial hot spots. These data suggest a mechanism whereby ABHD16A functions by altering phospholipid composition at ER-mitochondria MCSs. Our data present the first example of an ER membrane protein that regulates the recruitment of both fission and fusion machineries to mitochondria.

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“…192 Interestingly, in the context of viral infections, ABHD16A also displays a cryptic depalmitoylase activity and, in doing so, regulates the functions of interferoninducible transmembrane proteins. 193 Finally, the biochemical characterization of a distant orthologue of ABHD16A, human ABHD16B, has been recently reported. 194,195 Like ABHD16A, this protein also shows PS-selective phospholipase activity, albeit the PLA1type.…”

Section: Ps Lipase: α/β-Hydrolase Domain Containing Protein No 16a (A...mentioning

confidence: 99%

“…Via its PS lipase activity, this upregulated ABHD16A causes increased lyso-PS concentrations in these cancer cells, which enhances cell invasion and metastasis of gastric cancers . Interestingly, in the context of viral infections, ABHD16A also displays a cryptic depalmitoylase activity and, in doing so, regulates the functions of interferon-inducible transmembrane proteins …”

Section: Enzymes Metabolizing Lyso-pss In Mammalian Cells and Tissuesmentioning

confidence: 99%

Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases

Chakraborty,

Kamat

2024

Chem. Rev.

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Lysophosphatidylserine (lyso-PS) has emerged as yet another important signaling lysophospholipid in mammals, and deregulation in its metabolism has been directly linked to an array of human autoimmune and neurological disorders. It has an indispensable role in several biological processes in humans, and therefore, cellular concentrations of lyso-PS are tightly regulated to ensure optimal signaling and functioning in physiological settings. Given its biological importance, the past two decades have seen an explosion in the available literature toward our understanding of diverse aspects of lyso-PS metabolism and signaling and its association with human diseases. In this Review, we aim to comprehensively summarize different aspects of lyso-PS, such as its structure, biodistribution, chemical synthesis, and SAR studies with some synthetic analogs. From a biochemical perspective, we provide an exhaustive coverage of the diverse biological activities modulated by lyso-PSs, such as its metabolism and the receptors that respond to them in humans. We also briefly discuss the human diseases associated with aberrant lyso-PS metabolism and signaling and posit some future directions that may advance our understanding of lyso-PS-mediated mammalian physiology.

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ABHD16A Negatively Regulates the Palmitoylation and Antiviral Function of IFITM Proteins

Cited by 9 publications

References 58 publications

Pooled PPIseq: screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform

Pooled PPIseq: screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform

An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion

Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases

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