Massive palmitoylation-dependent endocytosis during reoxygenation of anoxic cardiac muscle

Lin, Mei Jung; Fine, Michael; Lu, Jui Yun; Hofmann, Sandra L.; Frazier, G.; Hilgemann, Donald W.

doi:10.7554/elife.01295

Cited by 66 publications

(93 citation statements)

References 55 publications

(78 reference statements)

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“…DHHC5 regulates Na pump density at the cell surface via MEND (8). Consistent with our previous investigation (9) we found no influence of PLM or its palmitoylation status on cell surface expression of the pump α-subunit (Fig.…”

Section: Discussionsupporting

confidence: 93%

“…DHHCs 2 and 3 possess notably little disorder, which may account for their tractability in cell-free systems (20). In some isoforms the region of C-tail disorder is relatively large (for example, DHHCs 1,5,8,and 14). Our experimental data together with these disorder predictions are consistent with previous reports that regions outside the cysteinerich domain are responsible for substrate recruitment to DHHCs (27)(28)(29).…”

Section: Discussionsupporting

confidence: 89%

“…An appreciation is now growing that protein palmitoylation turns over rapidly (in minutes) for certain proteins (4)(5)(6)(7)(8). For example, dynamic surface membrane protein palmitoylation by DHHC5 underlies a novel form of endocytosis, massive endocytosis (MEND), in which up to 70% of the cell surface membrane is internalized (7,8).…”

mentioning

confidence: 99%

“…For example, dynamic surface membrane protein palmitoylation by DHHC5 underlies a novel form of endocytosis, massive endocytosis (MEND), in which up to 70% of the cell surface membrane is internalized (7,8). Calcium overload leading to mitochondrial stress causes transient openings of the mitochondrial permeability transition pore (MPTP) and release of CoA into the cytoplasm, where it is acylated to form a substrate for DHHC5 to palmitoylate surface membrane proteins (7).…”

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confidence: 99%

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Substrate recognition by the cell surface palmitoyl transferase DHHC5

Howie

Reilly

Fraser

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

105

157

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The cardiac phosphoprotein phospholemman (PLM) regulates the cardiac sodium pump, activating the pump when phosphorylated and inhibiting it when palmitoylated. Protein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol, is catalyzed by the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases. The cell surface palmitoyl acyltransferase DHHC5 regulates a growing number of cellular processes, but relatively few DHHC5 substrates have been identified to date. We examined the expression of DHHC isoforms in ventricular muscle and report that DHHC5 is among the most abundantly expressed DHHCs in the heart and localizes to caveolin-enriched cell surface microdomains. DHHC5 coimmunoprecipitates with PLM in ventricular myocytes and transiently transfected cells. Overexpression and silencing experiments indicate that DHHC5 palmitoylates PLM at two juxtamembrane cysteines, C40 and C42, although C40 is the principal palmitoylation site. PLM interaction with and palmitoylation by DHHC5 is independent of the DHHC5 PSD-95/Discslarge/ZO-1 homology (PDZ) binding motif, but requires a ∼120 amino acid region of the DHHC5 intracellular C-tail immediately after the fourth transmembrane domain. PLM C42A but not PLM C40A inhibits the Na pump, indicating PLM palmitoylation at C40 but not C42 is required for PLM-mediated inhibition of pump activity. In conclusion, we demonstrate an enzyme-substrate relationship for DHHC5 and PLM and describe a means of substrate recruitment not hitherto described for this acyltransferase. We propose that PLM palmitoylation by DHHC5 promotes phospholipid interactions that inhibit the Na pump.phospholemman | sodium pump | palmitoylation | DHHC | ion transport P rotein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol via a thioester bond, is catalyzed by Asp-His-His-Cys motif-containing palmitoyl acyltransferases (DHHC-PATs); there are 23 human isoforms (1). These zinc-finger-containing enzymes typically have four transmembrane (TM) domains, with a conserved ∼50 amino acid cysteine-rich cytosolic core located between TM2 and -3, which contains a conserved DHHC motif, the active site. In contrast, the intracellular amino and carboxyl termini are poorly conserved, and likely contribute to DHHC isoform substrate selectivity (1). DHHC-PATs are expressed throughout the secretory pathway, but DHHC5 is widely recognized as one of very few cell-surfacelocalized PATs (2, 3). The final four amino acids of DHHC5 form a canonical class II PSD-95/Discs-large/ZO-1 homology (PDZ) binding motif, which interacts with postsynaptic density protein 95 (PSD-95) (2), although PSD-95 is not itself a DHHC5 substrate.An appreciation is now growing that protein palmitoylation turns over rapidly (in minutes) for certain proteins (4-8). For example, dynamic surface membrane protein palmitoylation by DHHC5 underlies a novel form of endocytosis, massive endocytosis (MEND), in which up to 70% of the cell surface membrane is internalized (7, 8). Calci...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Substrate recognition by the cell surface palmitoyl transferase DHHC5

Howie

Reilly

Fraser

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

105

157

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“…It has been reported that some cardiac proteins are palmitoylated, including Na pump regulatory subunit phospholemman and β1-adrenergic receptor (20)(21)(22). However, there is a lack of genetic evidence that protein palmitoylation plays a role in heart development and function.…”

mentioning

confidence: 98%

Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy

Zhou

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Protein palmitoylation regulates many aspects of cell function and is carried out by acyl transferases that contain zf-DHHC motifs. The in vivo physiological function of protein palmitoylation is largely unknown. Here we generated mice deficient in the acyl transferase Aph2 (Ablphilin 2 or zf-DHHC16) and demonstrated an essential role for Aph2 in embryonic/postnatal survival, eye development, and heart development. Aph2 −/− embryos and pups showed cardiomyopathy and cardiac defects including bradycardia. We identified phospholamban, a protein often associated with human cardiomyopathy, as an interacting partner and a substrate of Aph2. Aph2-mediated palmitoylation of phospholamban on cysteine 36 differentially alters its interaction with PKA and protein phosphatase 1 α, augmenting serine 16 phosphorylation, and regulates phospholamban pentamer formation. Aph2 deficiency results in phospholamban hypophosphorylation, a hyperinhibitory form. Ablation of phospholamban in Aph2 −/− mice histologically and functionally alleviated the heart defects. These findings establish Aph2 as a critical in vivo regulator of cardiac function and reveal roles for protein palmitoylation in the development of other organs including eyes.palmitoyl transferase | phospholamban | cardiac development | eye development | Aph2 gene

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DHHC5 facilitates oligodendrocyte development by palmitoylating and activating STAT3

Liu

et al. 2021

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Massive palmitoylation-dependent endocytosis during reoxygenation of anoxic cardiac muscle

Cited by 66 publications

References 55 publications

Substrate recognition by the cell surface palmitoyl transferase DHHC5

Substrate recognition by the cell surface palmitoyl transferase DHHC5

Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy

DHHC5 facilitates oligodendrocyte development by palmitoylating and activating STAT3

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