Table 4.
The summary of the role of lipidation in modulating protein functions
| Lipidation | Protein | The role of lipidation in modulating protein functions | Ref. |
|---|---|---|---|
| S-palmitoylation | CD36 | S-palmitoylation increases CD36 intracellular trafficking and the incorporation of CD36 into the PM by enhancing its hydrophobicity. | 86 |
| SCRIB | S-palmitoylation promotes SCRIB proper localisation to cell–cell junctions, and disrupting SCRIB S-palmitoylation by palmitoylation site mutation would cause a diffuse distribution of SCRIB in the cytosol. | 90 | |
| AMPAR | S-palmitoylation at TMD2 of AMPAR increases AMPAR internalisation and accumulation in Golgi, and depalmitoylation at this site promotes AMPAR to traffic from Golgi to the cell surface. The S-palmitoylation of C-terminal site regulates the interaction of AMPAR with 4.1N, and depalmitoylation increases the affinity with AMPAR-associated proteins such as 4.1N to keep AMPAR on the cell surface. | 92 | |
| FLT3 | S-palmitoylation keeps FLT3 internal tandem repeat localising to ER, while disrupting FLT3 internal tandem repeat S-palmitoylation by palmitoylation site mutation would increase its PM localisation, followed by activation of Akt, ERK and STAT5. | 93 | |
| PD-L1 | S-palmitoylation prevents PD-L1 from degradation. Blocking S-palmitoylation promotes its lysosomal degradation by inducing PD-L1 ubiquitination through the ESCRT-MVB pathway. | 98 | |
| Oct4 | Oct4A is a variant of Oct4. S-palmitoylation prevents Oct4A from lysosome degradation to maintain its protein stability, thereby maintaining the stemness of Oct4-mediated glioma stem cells. | 100 | |
| NOD2 | S-palmitoylation promotes NOD2 membrane recruitment and activation. Besides, S-palmitoylation prevents NOD2 from lysosome SQSTM1-mediated selective macroautophagic/autophagic degradation to maintain its protein stability. | 101 | |
| CLDN3 | S-palmitoylation is required for CLDN3 proper PM localisation and its protein stability, thereby promoting ovarian cancer progress. | 102 | |
| spike | DHHC20 and DHHC9 are responsible for palmitoylation of spike proteins in ER and Golgi, following in company with viral budding to mediate viral fusion and infection of host cells. | 34,145 | |
| Fas | S-palmitoylation prevents Fas from lysosome degradation to maintain its protein stability, thereby promoting Fas-mediated apoptosis pathway. | 103 | |
| NLRP3 | S-palmitoylation of NLRP3 promotes its chaperone-mediated autophagy and degradation, thereby impairing its protein stability and preventing sustained inflammation. | 104 | |
| S-palmitoylation | AEG-1 | S-palmitoylation of AEG-1 promotes its FBXW7-mediated ubiquitination and degradation. While disrupting AEG-1 S-palmitoylation by palmitoylation site mutation can weaken its binding to FBXW7 and increase its protein stability. | 83 |
| IFNGR1 | S-palmitoylation of IFNGR1 promotes its binding to AP3D1 and then lysosome degradation. | 105 | |
| CASP6 | S-palmitoylation increases the flexibility of its loop 4 and enhances the interaction between loop 4 and loop 2, which leads to the blockage of activation site. | 108 | |
| PSD95 | S-palmitoylation induces a conformational change of PSD95 from extended to compact, which leads to PSD95 binding directly to NMDAR and AMPAR subunits. | 109 | |
| STING | S-palmitoylation is required for STING activation in Golgi. Besides, STING S-palmitoylation enhances its interaction with VDAC2, thereby regulating tumour growth independent of innate immunity. | 110,112 | |
| cGAS | S-palmitoylation of cGAS reduces the interaction between cGAS and double-stranded DNA, thereby negatively regulating cGAS-mediated innate immune responses. | 116 | |
| STAT3 | S-palmitoylation of STAT3 allows STAT3 to traffic and translocate to the PM for subsequent phosphorylation, and then phosphorylated STAT3 is depalmitoylated by APT2, which leads to STAT3 detaching from the PM and transporting to nucleus to activate the downstream genes RORC and IL17A, thereby initiating differentiation of TH17 cells. | 117 | |
| AGK | S-palmitoylation of AGK promotes translocation of AGK into the PM and activation of the PI3K-Akt-mTOR signalling pathway, thereby modulating sunitinib sensitivity against RCC. | 119 | |
| ACE2 | S-palmitoylation and depalmitoylation of ACE2 is regulated by DHHC3 and APT1 for its PM targeting and extracellular vesicle secretion. | 147 | |
| GRK6 | S-palmitoylation of GRK6 promotes translocation of GRK6 into the PM and activation of the PI3K-Akt signalling pathway, thereby promoting LPS-induced inflammatory response. | 120 | |
| PCSK9 | S-palmitoylation of PCSK9 increases its affinity with PTEN and induces it to target lysosomes for degradation, thereby removing the inhibitory effect of PTEN on Akt signalling and leading to abnormal activation of Akt signalling. | 121 | |
| S-palmitoylation | β-catenin | S-palmitoylation protects β-catenin againstβ-Trcp mediated proteasomal degradation and activates DUSP14 by upregulating c-Myc, thereby boosting CRC progression. | 124 |
| MDH2 | S-palmitoylation increases the activity of the key tricarboxylic acid cycle enzyme MDH2 to support mitochondrial respiration and tumour cell proliferation, thereby promoting the malignancy of ovarian cancer. | 125 | |
| GLUT1 | S-palmitoylation promotes GLUT1 proper localisation to the PM for glucose transport, thereby assisting tumour cells in taking up nutrients to meet their high metabolic demands. | 126 | |
| HK1 | S-palmitoylation of HK1 promotes its proper localisation to the PM in hepatic stellate cells. In the presence of TSG101, HK1 is secreted extracellularly via vesicles and further taken up by hepatocellular carcinoma cells to promote tumour cell glycolysis. | 127 | |
| MC1R | S-palmitoylation of MC1R RHC variant can rescue its function and activate MC1R signalling, thereby promoting pigmentation and controlling melanomagenesis. | 128 | |
| mTOR | S-palmitoylation of mTOR reduces its stability in a time-dependent manner, thereby disturbing the PI3K/Akt/mTOR signalling pathway, inhibiting breast cancer proliferation and improving its resistance to neratinib. | 131 | |
| syt11 | S-palmitoylation of syt11promotes its localisation to the cell membrane rather than degradation in lysosomes, and this modification leads to enhanced binding of α-synuclein to the intracellular membranes and the abnormal aggregation of α-synuclein in PD neurons. | 135 | |
| N-myristoylation | PKA | N-myristoylation of PKA promotes its membrane association by increasing its affinity with membranes. | 178 |
| Gαi1 | N-myristoylation of Gαi1 promotes its association with ordered lipid microdomains with higher phosphatidylserine content on the PM. | 185 | |
| FSP1 | N-myristoylation of FSP1 promotes its membrane association and maintains its stability by evading the proteasome degradation pathway. | 186 | |
| VILIP3 | N-myristoylation of VILIP3 protects itself from lysosomal pathway-mediated degradation, thereby enhancing its stability and subsequent NFκB/Bcl-2 signalling. | 187 | |
| Calcineurin | N-myristoylation of Calcineurin could increase its thermal stability. | 188 | |
| N-myristoylation | c-Src | N-myristoylation of c-Src increases its association with ubiquitin E3 ligase and then promotes proteasome-mediated degradation of c-Src. | 192 |
| p60v-src | N-myristoylation of p60v-src promotes its binding to receptor SLC25A5, thereby interacting with the membrane to keep the transformation activity of the virus. | 193,194 | |
| Lck | N-myristoylation of Lck promotes its proper localisation to the PM and then interaction with TCR complex, therefore initiating and propagating the TCR signalling cascade. | 496 | |
| HO-2 | N-myristoylation of HO-2 is required for HO-2 binding to the myristic acid portion of Gag, and blocking HO-2 myristoylation would lead to an increase in viral replication. | 198 | |
| AMPK | N-myristoylation of AMPK is required for its lysosomal recruitment and activation, which suppresses overactivation of the mTORC1 pathway and T-cell differentiation into pro-inflammatory TH1 and TH17 helper T cells. | 209 | |
| ARF1 | N-myristoylation of ARF1 is required for its function as a major regulator of STING membrane trafficking. | 205 | |
| Neurl-1 | N-myristoylation of Neurl-1 is indispensable for the endocytosis and re-localisation on the PM of Notch ligand jagged 1. | 203 | |
| EZH2 | Myristoylated EZH2 binds STAT3 to recruit it to phase-separated droplets, thereby overactivating STAT3 pathway to promote lung cancer progression. | 210 | |
| LAMTOR1 | N-myristoylation of LAMTOR1 enhances its protein stability and lysosomal localisation, which leads to the activation of the mTORC1 pathway. | 211 | |
| ARF6 | N-myristoylation of ARF6 facilitates its budding from the Golgi and its translocation in the GTP-bound form, thereby transporting EGFR from Golgi to the PM. | 213 | |
| Akt | Myristoylated Akt induces increased leptin levels in 3T3-L1 adipocytes, thereby involving in the development of obesity. | 217 | |
| MARCKS | N-myristoylation of MARCKS increases its affinity with cell membranes. | 177 | |
| Nef | N-myristoylation of Nef promotes its binding to the PM, which results in rapid internalisation of CD4 and MHC-1 of on the T-cell surface, leading to their degradation in lysosomes. Besides, through interaction with AP-1, myristoylated Nef disrupts the membrane delivery of VAMP3 and TNFα-positive endosome compartments and impairs optimal phagosome formation, thereby inhibiting macrophage phagocytosis. | 220–222 | |
| Gag | N-myristoylation of Gag on its N-terminal matrix domain promotes Gag targeting the PM and anchoring. | 195,196 | |
| N-myristoylation | NKD2 | N-myristoylation of NKD2 promotes its transport to the PM and interacting with Dvl-1, therefore leading to mutual ubiquitin-mediated proteasomal degradation and losing the ability to antagonise Wnt-beta-catenin activity. | 201,497 |
| LYN | N-myristoylation of LYN promotes its proper localisation to the PM and subsequent phosphorylation, thereby interacting with BCR to regulate B-cell activation and function. | 498,499 | |
| HGAL | N-myristoylation of LYN promotes its proper localisation to cellular membrane raft microdomains, facilitating the interaction with SYK and modulation of the BCR activation and signalling. | 500 | |
| S-prenylation | Ras | N-Ras, H-Ras, and K-Ras4a undergo prenylation and palmitoylation for anchoring to the PM via two hydrophobic moieties. Ras4b anchors to the PM through its farnesyl group combined with a lysine-rich polybasic sequence. | 266 |
| MSPs | MSPs, such as MSP-1, MSP-2 and others are spread over the surface of Plasmodium merozoites, contributing to parasite survival and invasion. | 419 | |
| Rac1 | Geranylgeranylation and subsequent palmitoylation of Rac1 is required for its translocation to the mitochondria-associated endoplasmic reticulum membrane (MAM), where Rac1 continues to limit the interaction of mitochondrial antiviral signalling proteins with Trim31, thereby inhibiting MAVS ubiquitination, aggregation and activation to prime antiviral immune response. | 267 | |
| CDC42 | Geranylgeranyation of CDC42 is crucial for the interaction of CDC42 with its chaperone protein RHOGDI. The binding of RHOGDI to CDC42 not only facilitates correct membrane association of the Cdc42, but also protects it from degradation. | 277,278 | |
| Rheb | Farnesylation of Rheb overactivates mTORC1 signalling, and thus leading to cardiomyocyte hypertrophy. | 285 | |
| Rab | Dual geranylgeranylation of Rab is vital for the proper transport and localisation of Notch signalling elements. Incorrect trafficking of Notch signalling components caused by mislocalization of Rabs will in turns lead to the Notch signalling defects. | 288 | |
| Delta virus large antigen | Delta virus large antigen is prenylated, which is essential to anchor to the HBsAg and be packaged into virus particles for HDV particle formation. | 301 | |
| Ykt6 | Farnesylation of Ykt6 induces a more compact and stable structure, thereby increasing its stability. | 276 | |
| GPI anchor | FOLR1 | The GPI-anchored protein FOLR1 mediates folate uptake for cell growth. When GPI-anchor of the folate receptors is replaced with transmembrane and cytosolic portions, the uptake efficiency of folate is significantly reduced. It also plays a significant role in modulating JAK-STAT3 signalling and ERK1/2 signalling. | 397–399 |
| CD14 | CD14 is a typical GPI-anchored glycoprotein. After recognising and binding to LPS, CD14 transfers LPS to MD-2 of the TLR4/MD-2 complex to promote TLR4 dimerisation. TLR4 dimerisation further induces the formation of Myddosomes based on MyD88, which triggers a signalling cascade, leading to activation of NF-κB and MAPK pathways. | 392,393 | |
| MSPs | MSPs, such as MSP-1, MSP-2 and others are spread over the surface of Plasmodium merozoites, contributing to parasite survival and invasion. | 419 | |
| PrPC | GPI is indispensable for PrPC to protect and repair neuronal cytoskeleton and neuronal communication. | 409 | |
| ART2 | ART2 is a GPI-anchored exonuclease that uses free NAD+ to mono-ADP-ribosylate the P2X7 receptor on CD8 T cells, leading to NAD-induced cell death and a reduction of the P2X7R + CD8 + T-cell subpopulation in the tumour microenvironment. | 394,395 | |
| NCAM | NCAM is a typical adhesion molecule, which regulates cell–cell adhesion by homophilic and heterophilic interactions to regulate the development and plasticity of the nervous system. | 396 | |
| GPAA1 | As a typical GPI-AP, GPAA1 enhances lipid raft formation to support the interaction between EGFR and ERBB2, which further activates downstream Akt signalling to enhance the proliferation of cancer cell. | 403 | |
| CD109 | CD109 is a GPI glycoprotein that can be expressed on the cell surface and enriched in lipid rafts or released extracellularly with exosomes. CD109 involves in TGF‐β signalling, EGFR-Akt-mTOR signalling, JAK-STAT3 signalling and YAP/TAZ signalling. | 386,388,390 | |
| uPAR | As a typical GPI-AP, uPAP binds to uPA, and then uPA cleaves plasminogen to generate the active protease plasmin, which further activates MMPs to degrade ECM components and promote tumour cell migration and invasion. Besides, uPAR–α5β1 integrin interaction signals to FAK and then activates EGFR, and uPAR–β1 integrin–EGFR signalling enhances ERK activation to promote cancer cell proliferation. | 404,405 | |
| GPI-anchor | CD55 | CD55 is a complement regulator to prevent activated complement toxicity. The CD55-defective PNH red blood cells lack the self-protective complement regulatory factors, and thus are highly sensitive to complement activation, which results in intravascular haemolysis. | 407,408 |
| CD59 | CD59 is a complement regulator to prevent activated complement toxicity. The CD59-defective PNH red blood cells lack the self-protective complement regulatory factors, and thus are highly sensitive to complement activation, which results in intravascular haemolysis. | 407,408 | |
| Cholesterylation | Hedgehog | Cholesterylation is required for Hedgehog to target the PM. | 438 |
| SMO | Cholesterylation is required for SMO enriching at the cell surface and subsequent Hedehog signalling. Abolishment of cholesterylation by mutation of D95 residue on SMO results in reduced Hh-stimulated ciliary localisation and compromised Hedehog signal transduction. | 443 |
PM plasma membrane, ER endoplasmic reticulum, RCC renal cell carcinoma, CRC colorectal cancer, PD Parkinson’s disease