Affinage

ZDHHC7

Palmitoyltransferase ZDHHC7 · UniProt Q9NXF8

Length
308 aa
Mass
35.1 kDa
Annotated
2026-06-11
13 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZDHHC7 is a Golgi-localized DHHC-family palmitoyl acyltransferase that S-palmitoylates a diverse set of substrate proteins to control their membrane targeting and downstream signaling across epithelial polarity, innate immunity, autophagy, and metabolism (PMID:27380321, PMID:38583156, PMID:39087410). Mechanistically, ZDHHC7 attaches palmitate to specific cysteines on its substrates: it palmitoylates Scribble to drive its targeting to cell-cell junctions, sustaining epithelial polarity and tumor suppression, such that its loss causes SCRIB mislocalization, YAP activation, and HRas(V12)-driven invasion (PMID:27380321); it palmitoylates NLRP3 at Cys126 to position the sensor on the trans-Golgi network and enable ASC recruitment and inflammasome activation (PMID:38583156); and it palmitoylates ATG16L1 at Cys153 to promote ATG16L1-WIPI2B and ATG16L1-RAB33B complex assembly, LC3 lipidation, and autophagosome formation (PMID:39087410). The same enzymatic logic extends to the small GTPase ARL15, which ZDHHC7 (together with ZDHHC3) triple-acylates at Cys17/Cys22/Cys23 to maintain its membrane association (PMID:41999893). Through substrate-specific palmitoylation ZDHHC7 also governs hepatic CD36 plasma-membrane delivery in NASH downstream of KLF10 (PMID:35492028), antiviral restriction by palmitoylating the PRRSV protein Nsp10 to weaken its RNA binding (PMID:41671757), and hippocampal synaptic plasticity and stress-related behavior (PMID:31183559). In prostate cancer cells ZDHHC7 suppresses androgen receptor transcription and tumor growth (PMID:37198397), and in models of Alzheimer's disease elevated hippocampal zDHHC7 driven by a FoxO1 epigenetic mechanism palmitoylates BACE1 and contributes to cognitive deficits (PMID:39589870).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2016 High

    Established ZDHHC7 as the major acyltransferase for Scribble, answering how a polarity scaffold is targeted to junctions and linking ZDHHC7 to tumor suppression.

    Evidence Chemical reporter palmitoylation assay, ZDHHC7 knockout, palmitoylation-deficient SCRIB mutants, and cell polarity/invasion assays

    PMID:27380321

    Open questions at the time
    • Does not define the structural basis of substrate selection
    • Other ZDHHC7 substrates not addressed
  2. 2019 Medium

    Showed ZDHHC7 is required for hippocampal excitatory transmission and synaptic plasticity in vivo, with sex-specific behavioral effects, placing palmitoylation in neuronal circuit function.

    Evidence Constitutive Zdhhc7 knockout mouse with electrophysiology, behavior, and fiber tractography

    PMID:31183559

    Open questions at the time
    • Direct neuronal substrate not identified
    • Link to sex steroid receptors inferred, not demonstrated
  3. 2021 Low

    Extended the neuronal role by linking ZDHHC7 to stress-dependent plasticity and estrogen receptor expression, but the molecular connection remained inferential.

    Evidence Zdhhc7-KO mouse with electrophysiology, diffusion tensor imaging, and ER mRNA quantification under acute stress

    PMID:33880616

    Open questions at the time
    • Estrogen receptor pathway link inferred rather than shown by palmitoylation assay
    • No identified palmitoylated substrate
  4. 2022 Medium

    Defined a KLF10→ZDHHC7→CD36 axis explaining how ZDHHC7 promotes hepatic lipid uptake, connecting the enzyme to NASH pathogenesis.

    Evidence Hepatocyte-specific gain/loss-of-function mouse models, CD36 palmitoylation assay, membrane fractionation, diet-induced NASH

    PMID:35492028

    Open questions at the time
    • CD36 palmitoylation site not mapped
    • Single lab
  5. 2023 Medium

    Revealed an unexpected non-canonical role for ZDHHC7 in suppressing androgen receptor transcription and prostate tumor growth.

    Evidence RNA-seq, knockdown/overexpression, AR transcription/protein assays, xenograft model

    PMID:37198397

    Open questions at the time
    • Molecular mechanism of AR transcriptional repression unresolved
    • Unclear whether this depends on acyltransferase activity
  6. 2024 High

    Mapped substrate-specific palmitoylation events placing ZDHHC7 in inflammasome activation (NLRP3 Cys126/TGN), autophagosome formation (ATG16L1 Cys153), and AD-associated BACE1 modification.

    Evidence Site-directed mutagenesis, KO/rescue, acyl-biotin exchange, localization imaging, in vivo inflammasome and cognitive readouts

    PMID:38583156 PMID:39087410 PMID:39589870

    Open questions at the time
    • How ZDHHC7 selects between these substrates is unknown
    • BACE1 study links palmitoylation to Aβ association but not causation
  7. 2025 Low

    Identified a dynamic SPRY4 palmitoylation-depalmitoylation cycle (ZDHHC7/PPT1) modulating MAPK signaling and chemoresistance in osteosarcoma.

    Evidence Palmitoylation assays, MAPK readouts, drug resistance assays, single-cell analysis

    PMID:40416361

    Open questions at the time
    • No mutagenesis or reconstitution explicitly described
    • Palmitoylation site on SPRY4 not defined
  8. 2026 High

    Demonstrated ZDHHC7 (with ZDHHC3) triple-acylates ARL15 to maintain membrane association, and that ZDHHC7 restricts PRRSV by palmitoylating Nsp10 to weaken RNA binding, with the virus encoding countermeasures.

    Evidence Acyl-PEGyl exchange, dual-enzyme CRISPR KO, cysteine-to-serine mutagenesis, fractionation, and antiviral replication/RNA-binding assays with cleavage-resistant mutants

    PMID:41671757 PMID:41999893

    Open questions at the time
    • Functional consequence of ARL15 acylation downstream of membrane targeting not defined
    • PRRSV mechanism in non-veterinary contexts untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • What determines ZDHHC7 substrate specificity across this broad and functionally divergent substrate set, and how its activity is regulated in different tissues, remains unresolved.
  • No structural model of substrate recognition in the corpus
  • Regulation of ZDHHC7 expression/activity across tissues incompletely defined
  • Acyltransferase-dependence of some phenotypes (e.g., AR suppression) unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005794 Golgi apparatus 2
Pathway
GO:0140096 catalytic activity, acting on a protein 3

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 ZDHHC7 is the major palmitoyl acyltransferase that S-palmitoylates Scribble (SCRIB) at conserved cysteine residues, which is required for SCRIB membrane targeting to cell-cell junctions, maintenance of epithelial cell polarity, and tumor suppression. Knockout of ZDHHC7 causes SCRIB mislocalization and YAP activation, and disrupts SCRIB's suppressive activities in HRas(V12)-induced cell invasion. Chemical reporter palmitoylation assay, ZDHHC7 knockout, palmitoylation-deficient SCRIB mutants, cell polarity assays, invasion assays Nature chemical biology High 27380321
2024 ZDHHC7 palmitoylates NLRP3 at Cys126, promoting NLRP3 localization on the trans-Golgi network (TGN) at rest and on dispersed TGN upon activation, which is required for recruitment and oligomerization of the adaptor ASC and full inflammasome activation in macrophages and in vivo. ZDHHC7 knockout, pharmacological inhibition, Cys126 site mutation, palmitoylation assay, subcellular localization imaging, ASC oligomerization assay, in vivo inflammasome activation Cell reports High 38583156
2024 ZDHHC7 S-palmitoylates ATG16L1 at Cys153; this palmitoylation enhances formation of the ATG16L1-WIPI2B and ATG16L1-RAB33B complexes on the phagophore, facilitating LC3 lipidation and autophagosome formation. Acyl-biotin exchange assay, ATG16L1-KO HeLa cell rescue with wild-type vs. C153S mutant, ZDHHC7 overexpression/deletion, LC3-II immunoblot, co-immunoprecipitation, transmission electron microscopy Autophagy High 39087410
2023 ZDHHC7 inhibits androgen receptor (AR) gene transcription, thereby reducing AR protein levels and abolishing AR signaling in prostate cancer cells; ZDHHC7 depletion increases oncogenic properties while ZDHHC7 restoration suppresses proliferation and invasion in vitro and tumor growth in vivo. RNA-seq, ZDHHC7 knockdown/overexpression, AR transcription and protein level assays, xenograft tumor model Oncogene Medium 37198397
2022 The transcription factor KLF10 transcriptionally activates ZDHHC7 expression, which then palmitoylates CD36, promoting its plasma membrane localization and driving hepatic lipid accumulation and inflammation in NASH pathogenesis. Transcriptomic analysis, gain/loss-of-function in hepatocyte-specific mouse models, CD36 palmitoylation assay, membrane fractionation, diet-induced NASH model EMBO reports Medium 35492028
2019 ZDHHC7 deficiency in mice impairs excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes; it also causes sex-specific effects on medial prefrontal cortical synaptic transmission and anxiety-related behavior (females only), consistent with a role in palmitoylation of sex steroid receptors linking them to membrane microdomains. Constitutive Zdhhc7 knockout mouse, behavioral tests, electrophysiology, protein analyses, diffusion tensor-based fiber tractography neuroimaging Brain structure & function Medium 31183559
2024 zDHHC7 expression and protein S-palmitoylation are elevated in hippocampi of 3×Tg-AD mice and post-mortem AD patients; hippocampal silencing of zDHHC7 prevents cognitive deficits in 3×Tg-AD mice; a FoxO1-mediated epigenetic mechanism drives zDHHC7 expression in response to brain insulin resistance; and S-palmitoylation of BACE1 (Beta-Secretase 1) by zDHHC7 is associated with Aβ1-42 load. zDHHC7 hippocampal silencing (knockdown) in 3×Tg-AD mice, cognitive behavior tests, 2-bromopalmitate pharmacological inhibition, palmitoylation assays, human post-mortem tissue analysis Proceedings of the National Academy of Sciences of the United States of America Medium 39589870
2025 ZDHHC7 palmitoylates Sprouty 4 (SPRY4), and this modification is reversed by palmitoyl-protein thioesterase 1 (PPT1); the dynamic palmitoylation-depalmitoylation cycle of SPRY4 modulates MAPK signaling and affects tumor cell proliferation, migration, apoptosis, and cisplatin resistance in osteosarcoma cells. In vitro and in vivo experiments, single-cell analysis, palmitoylation assays, MAPK signaling readouts, drug resistance assays Research (Washington, D.C.) Low 40416361
2026 ZDHHC7 and ZDHHC3 (both Golgi-localized S-acyltransferases) mediate triple S-acylation of the small GTPase ARL15 at Cys17, Cys22, and Cys23; loss of S-acylation disrupts ARL15 membrane association, redistributing it from membranes to the cytosol. Acyl-PEGyl exchange gel-shift assay, siRNA knockdown, CRISPR/Cas9 gene disruption, confocal imaging, subcellular fractionation, cysteine-to-serine mutagenesis The Journal of biological chemistry High 41999893
2026 ZDHHC7 S-palmitoylates the PRRSV nonstructural protein Nsp10 in an acyltransferase-dependent manner, weakening Nsp10 binding to viral RNA and restricting PRRSV replication; PRRSV counteracts this by having Nsp4 cleave ZDHHC7 at E226 (abolishing palmitoylation of Nsp10, STING, and MAVS), and by Nsp2/GP5 inducing APT1 (depalmitoylase) via NFATC3 to reverse Nsp10 palmitoylation. Palmitoylation assays, ZDHHC7 overexpression/mutation (E226A cleavage-resistant), viral replication assays, RNA-protein binding assays, transcription factor analysis Research in veterinary science Medium 41671757
2021 ZDHHC7 deficiency impairs synaptic plasticity in mice of both sexes; after acute stress, male Zdhhc7-KO mice show reduced mean fiber lengths of the medioventral hippocampus, while acute stress improves synaptic plasticity in female (but not male) mice; estrogen receptor α and β mRNA levels are reduced by acute stress in male mice regardless of genotype, consistent with ZDHHC7 modulating stress responses partly via estrogen receptor-mediated pathways. Zdhhc7 knockout mouse, electrophysiology, diffusion tensor imaging, mRNA expression analysis (qPCR), behavioral tests Brain structure & function Low 33880616

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity. Nature chemical biology 97 27380321
2024 NLRP3 Cys126 palmitoylation by ZDHHC7 promotes inflammasome activation. Cell reports 78 38583156
2024 ZDHHC7-mediated S-palmitoylation of ATG16L1 facilitates LC3 lipidation and autophagosome formation. Autophagy 35 39087410
2023 Palmitoyl acyltransferase ZDHHC7 inhibits androgen receptor and suppresses prostate cancer. Oncogene 26 37198397
2022 KLF10 promotes nonalcoholic steatohepatitis progression through transcriptional activation of zDHHC7. EMBO reports 26 35492028
2024 Inhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 19 39589870
2019 Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner. Brain structure & function 16 31183559
2021 Brain microstructural changes in mice persist in adulthood and are modulated by the palmitoyl acyltransferase ZDHHC7. The European journal of neuroscience 14 34355442
2025 Dual Regulation of Sprouty 4 Palmitoylation by ZDHHC7 and Palmitoyl-Protein Thioesterase 1: A Potential Therapeutic Strategy for Cisplatin-Resistant Osteosarcoma. Research (Washington, D.C.) 11 40416361
2021 Acute stress reveals different impacts in male and female Zdhhc7-deficient mice. Brain structure & function 8 33880616
2025 Deficiency of the palmitoyl acyltransferase ZDHHC7 modulates depression-like behaviour in female mice after a mild chronic stress paradigm. Translational psychiatry 1 39856044
2026 S-palmitoylation of the viral Nsp10 by ZDHHC7 restricts PRRSV replication but is counteracted by Nsp2, Nsp4 and GP5. Research in veterinary science 0 41671757
2026 S-acylation and membrane localization of the small GTPase ARL15 are mediated by the Golgi S-acyltransferases ZDHHC7 and ZDHHC3. The Journal of biological chemistry 0 41999893

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