Table 3 Genetic evidence for lipidation-related enzymes in diseases

DHHC1

Zdhhc1(−/−) mice

Zdhhc1(−/−) mice have lower cytokine levels and higher virus titre in the brain, indicating that DHHC1 is vital in mediating MITA/STING-dependent immune signalling against DNA viruses.

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DHHC2

Zdhhc2(−/−) mice

Zdhhc2(−/−) mice inhibit plasmacytoid dendritic cell accumulation, impair T-cell activation and inhibit IFN-α production in the lesioned skin during psoriasis modelling, indicating that DHHC2 is vital in triggering immune response against inflammatory disorders.

¹⁴⁰

DHHC3

Zdhhc3(−/−) mice

Binding of DHHC3 to UL20 is significant for virus infectivity and viral pathogenesis. HSV-1-infected Zdhhc3(−/−) mice have lower virus replication and decreased HSV-1 latency reactivation, indicating that the absence of DHHC3 blocks UL20 palmitoylation and then disturbs cytoplasmic envelopment of virions and virus egress.

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DHHC3

Cardiomyocyte-specific transgenic mice overexpressing zDHHC3

DHHC3 promotes Rac1 signalling and maladaptive cardiac remodelling. Cardiomyocyte-specific transgenic mice overexpressing zDHHC3 exhibit enhanced Rac1 S-palmitoylation and downstream hypertrophic signalling, ultimately leading to cardiac disease.

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DHHC4

Zdhhc4(−/−) mice

Palmitoylation of CD36 is meditated by DHHC4. Zdhhc4(−/−) mice exhibit decreased fatty acid uptake activity in adipose tissues and are intolerant to acute cold exposure, indicating that DHHC4 plays a crucial role in regulating fatty acid uptake by targeting CD36.

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DHHC5

Zdhhc5^flox/flox mice

Palmitoylation of CD36 is also meditated by DHHC5. Zdhhc5^flox/flox mice also exhibit decreased fatty acid uptake activity in adipose tissues and are intolerant to acute cold exposure, indicating that DHHC5 also plays a crucial role in regulating fatty acid uptake by targeting CD36.

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DHHC5

ZDHHC5 knockout mice (LysM-Cre /ZDHHC5^fl/fl mice)

Palmitoylation of NOD1/2 is meditated by DHHC5.

LysM-Cre /ZDHHC5^fl/fl mice exhibit impaired NOD1/2–dependent activation of NF-kB and p38 MAPK signalling, indicating that palmitoylation of NOD1/2 meditated by DHHC5 is important in triggering immune response against peptidoglycans.

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DHHC7

Zdhhc7(−/−) mice

Various synaptic and extrasynaptic proteins are meditated by DHHC7. Zdhhc7(−/−) mice exhibit impaired synaptic plasticity, while acute stress improves it only in females, but not in male mice, indicating that the role of DHHC7 in stress responses is sex-specific.

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DHHC8

Zdhhc8(−/−) mice

DHHC8 deficiency is related to specific cognitive deficits and schizophrenia. Zdhhc8(−/−) mice exhibit impaired axonal growth, indicating that DHHC8 is important to modulate neuronal polarity.

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DHHC9

Zdhhc9(−/−) mice

DHHC9 is associated with neurodevelopmental disorders. Zdhhc9(−/−) mice exhibit increased seizure activity and synaptic excitability, indicating that DHHC9 contributes to the pathogenesis of intellectual disability and epilepsy.

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DHHC11

Zdhhc11(−/−) mice

DHHC11 is a positive regulator of DNA virus-triggered signalling. Zdhhc11(−/−) mice exhibit lower serum cytokine levels and are more sensitive to HSV-1-induced death, indicating that DHHC11 contributes to host defence against HSV-1 infection.

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DHHC13

Transgenic DHHC13 mice

Palmitoylation of MC1R is meditated by DHHC13, which enhances DNA repair after ultraviolet irradiation. Transgenic DHHC13 mice have increased MC1R palmitoylation, rescue MC1R RHC-induced “red hair” phenotype and inhibit UVB-induced melanomagenesis in redheads, indicating that DHHC13-activated MC1R palmitoylation contributes to melanoma prevention.

¹²⁹

DHHC13

Zdhhc13^skc4 mice with a deficiency in DHHC13

Zdhhc13^skc4 mice exhibit hyperproliferation of the epidermis and disturb cornification, cyclic alopecia and skin abnormalities, indicating that DHHC13 plays a crucial role in hair anchoring and skin barrier function.

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DHHC15

Zdhhc15(−/−) mice

Genetic deficiency of DHHC15 is associated with intellectual disability and behavioural anomalies. Zdhhc15(−/−) mice exhibit increased tissue and extracellular dopamine levels in ventral striatum and novelty-induced locomotion in open field, indicating that DHHC15-mediated palmitoylation contributes to the regulation of dopamine in the striatum.

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DHHC17

Zdhhc17(−/−) mice

DHHC17 regulates huntingtin protein and various synaptic protein. Zdhhc17(−/−) mice exhibit huntington disease-like neuropathology with corresponding behavioural, biochemical and neuropathological defects. Besides, behavioural and electrophysiological measures also suggest that Zdhhc17(−/−) mice have striatal dysfunction, astrogliosis and microgliosis, indicating that DHHC17 is essential for the maintenance of life and neuronal integrity.

^484,485

DHHC19

Zdhhc19(−/−) mice

Zdhhc19−/− mice exhibit decreased testicular weight ratio, lower number and motility of the sperm and abnormal morphology. Zdhhc19 knockout male mice are sterile, and those results indicate that DHHC19 is vital in spermatogenesis and sperm functions.

^486,487

DHHC21

Zdhhc21(−/−) mice

DHHC21 is involved in mediating signalling events required for gut hyperpermeability induced by inflammation. Zdhhc21(−/−) mice exhibit attenuated hyperpermeability response in an experimental model of thermal injury, indicating that targeting DHHC21 for burn-induced intestinal barrier dysfunction has therapeutic potential.

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APT1

APT1 knockout mice

APT1 is able to depalmitoylate palmitoylated proteins implicated in exocytosis. APT1 knockout mice exhibit increased glucose-stimulated insulin secretion and β cell failure, indicating that APT1 is regulated in human islets and APT1 deficiency leads to β cell failure and type 2 diabetes.

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NMT1

Heterozygous (+/−) Nmt1-deficient mice;

Homozygous (−/−) Nmt1-deficient mouse

NMT1 plays an essential role in the early development of mouse embryo. Heterozygous (+/−) Nmt1-deficient mice exhibit suppressed macrophage colony forming and homozygous (−/−) Nmt1-deficient mouse embryonic stem cells exhibit a drastic reduction of macrophages after being stimulated by M-CSF, indicating that NMT1 is critical for proper monocytic differentiation.

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FTase

FTase-deficient mice (FTΔ;RERTert/ert mice)

FTΔ;RERTert/ert mice exhibit delayed wound healing and maturation defects in erythroid cells. In tumour model, FTΔ;RERTert/ert mice exhibit reduced tumour development, which sheds light on the role of FTase in embryonic and tumour development.

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FTase

Conditional FTase knockout mice (Fntb^fl/ΔKL mice)

FTase-meditated farnesylation of HDJ2 and H-RAS promotes tumourigenesis. Fntb^fl/ΔKL mice exhibit reduced tumour development and increased survival with K-RAS-induced lung cancer.

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FTase

Keratinocyte-specific Fntb knockout mice (Fntb^Δ/Δ mice)

Fntb^Δ/Δ mice exhibit small and dysmorphic hair follicles and develop severe alopecia, while their skin barrier function is normal. Keratinocytes from Fntb^Δ/Δ mice are unable to proliferate, indicating that FTase is essential for the homeostasis of skin keratinocytes.

⁴⁹¹

GGTase-I

Conditional FTase and GGTase-I knockout mice (Fntb^fl/ΔPggt1^bfl/ΔKL mice)

Fntb^fl/ΔPggt1^bfl/Δ KL mice exhibit a far greater inhibitory effect on K-RAS-induced tumours than conditional FTase knockout mice, indicating that simultaneous inhibition of FTase and GGTase-I has a stronger antitumour effect and is therapeutically useful.

³⁴⁵

GGTase-I

Keratinocyte-specific Pggt1b knockout mice (Pggt1b^Δ/Δ mice)

Pggt1b^Δ/Δ mice exhibit stunted hair follicles and invariably die soon after birth. And keratinocytes from Pggt1b^Δ/Δ mice are unable to proliferate, indicating that GGTase-I is also essential for the homeostasis of skin keratinocytes.

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GGTase-I

Podocyte-specific GGTase-I knockout mice

GGTase-I-mediated actin cytoskeleton is essential to maintaining podocyte function. Podocyte-specific GGTase-I knockout mice exhibit progressive albuminuria and foot process effacement due to dysregulation of the actin cytoskeleton, indicating that GGTase-I-mediated geranylgeranylation is crucial in the maintenance of glomerular integrity and function by regulating actin cytoskeleton.

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GGTase-I

GGTase-I-deficient mice (Pggt1b^Δ/Δ mice)

Pggt1b^Δ/Δ mice exhibit enhanced inflammatory responses and severe rheumatoid arthritis, while Rac1 knockout prevents arthritis in GGTase-I-deficient mice, indicating that prenylation suppressed innate immune responses by blocking Rac1 effector interactions.

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GGTase-I

GGTase-I-deficient mice (Pggt1b^fl/flLyz2-Cre mice)

Geranylgeranylation involves in the antiviral innate immune response. Pggt1b^fl/flLyz2-Cre mice exhibit improved survival upon lethal influenza A virus infection, indicating that impairment of protein geranylgeranylation contributes to part of the antiviral effect.

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GGTase-I

T-cell-specific GGTase-I knockout mice (Pggt1b^ΔCD4 mice)

GGTase-I-mediated prenylation regulates T-cell intestine localisation and chronic inflammation. Pggt1b^ΔCD4 mice develop spontaneous colitis through impairing RHOA function and therefore increasing integrin alpha4beta7 expression as well as colon localisation, indicating that GGTase-I-mediated prenylation of RHOA is essential for its activation and colonic T-cell localisation.

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GGTase-I

Pggt1b^−/− mice

Prenylation plays a crucial role in crthymocyte egress and immune homeostasis. Pggt1b^−/− mice exhibit marked defects in thymocyte egress and decreased T-cell lymphopenia in peripheral lymphoid organs, while Fntb − /− mice exhibit reduced percentages and numbers of PLN CD4+ and CD8 + T cells, revealing unique roles of prenylation in immune homeostasis mediated by GGTase-I or FTase, respectively.

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PGAP4

PGAP4 knockout mice

PGAP4 catalyses the first step of GalNAc side chain generation. PGAP4 knockout mice exhibit abnormal bone formation, reduced locomotion activity as well as impaired memory formation, and they are more vulnerable to prion diseases, indicating that PGAP4-mediated GalNAc side chain is indispensable for various physiological function, especially in bone and the brain.

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PGAP6

Pgap6 knockout mice

Pgap6 is involved in GPI-AP processing and regulates CRIPTO shedding. Pgap6 knockout mice exhibit defects in early embryonic development, especially anterior–posterior axis formation in embryos, indicating Pgap6-mediated CRIPTO shedding plays an essential role in embryonic development.

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