ZDHHC1

Last update 08 May 2025

Basic Info

Synonyms

C16orf1, DHHC domain-containing cysteine-rich protein 1, DHHC-1

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Introduction

Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as NCDN and NLRP3 (PubMed:39173637). Has a palmitoyltransferase activity toward NCDN and regulates NCDN association with endosome membranes through this palmitoylation (By similarity). Acts as an activator of the NLRP3 inflammasome by mediating palmitoylation of 'Cys-130' and 'Cys-958' of NLRP3, thereby promoting NLRP3 phosphorylation and activation by NEK7 (PubMed:39173637). Has also a palmitoyltransferase activity-independent function in DNA virus-triggered and CGAS-mediated innate immune response (PubMed:25299331). Functions as an activator of STING1 by promoting its cGAMP-induced oligomerization and the recruitment of downstream signaling components (PubMed:25299331).

100 Clinical Results associated with ZDHHC1

100 Translational Medicine associated with ZDHHC1

0 Patents (Medical) associated with ZDHHC1

Literatures (Medical) associated with ZDHHC1

01 Feb 2025·Journal of Neurochemistry

Palmitoylation regulates norepinephrine transporter uptake, surface localization, and total expression with pathogenic implications in postural orthostatic tachycardia syndrome

Article

Author: Foster, James D. ; Shetty, Madhur ; Brown, Christopher R.

AbstractPostural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasis via the reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. In this study, we reveal NET is palmitoylated in male Sprague–Dawley rats and Lilly Laboratory Cell Porcine Kidney (LLC‐PK1) cells. S‐palmitoylation, or the addition of a 16‐carbon saturated fatty acid, is a reversible post‐translational modification responsible for the regulation of numerous biological mechanisms. We found that LLC‐PK1 NET is dynamically palmitoylated, and that inhibition with the palmitoyl acyltransferase (DHHC) inhibitor, 2‐bromopalmitate (2BP) results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely by a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co‐expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted wild‐type (WT) hNET palmitoylation and elevated NET protein levels. The POTS‐associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression, we co‐expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N‐terminal immuno‐detectable forms and fragments. Elimination of a potential palmitoylation site at cysteine 44 in the N‐terminal tail of hNET resulted in a low expression phenotype mimicking the A457P hNET variant. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of adrenergic disorders like POTS.

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01 Feb 2025·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Zdhhc1 deficiency mitigates foam cell formation and atherosclerosis by inhibiting PI3K-Akt-mTOR signaling pathway through facilitating the nuclear translocation of p110α

Article

Author: Li, Sainan ; Lu, Beijia ; Lawrence, Toby ; Lu, Liaoxun ; Qi, Yingcheng ; Huang, Rong ; Zhou, Binhui ; Liu, Tingting ; Wang, Ying ; Li, Tianhan ; Fu, Rui ; Liang, Yinming ; Qiu, Juanjuan ; Li, Wushan ; Tian, Shuanghua ; Liu, Yang ; Ma, Haoyuan ; Liu, Qiaoli ; Gu, Yanrong ; Zhang, Lichen ; Zhang, Mengjie ; Zhang, Bowen ; Kong, Eryan

Monocyte-to-macrophage differentiation and subsequent foam cell formation are key processes that contribute to plaque build-up during the progression of atherosclerotic lesions. Palmitoylation enzymes are known to play pivotal roles in the development and progression of inflammatory diseases. However, their specific impact on atherosclerosis development remains unclear. In this study, we discovered that the knockout of zDHHC1 in THP-1 cells, as well as Zdhhc1 in mice, markedly reduces the uptake of oxidized low-density lipoprotein (ox-LDL) by macrophages, thereby inhibiting foam cell formation. Moreover, the absence of Zdhhc1 in ApoE^-/- mice significantly suppresses atherosclerotic plaque formation. Mass spectrometry coupled with bioinformatic analysis revealed an enrichment of the PI3K-Akt-mTOR signaling pathway. Consistent with this, we observed that knockout of zDHHC1 significantly decreases the palmitoylation levels of p110α, a crucial subunit of PI3K. Notably, the deletion of Zdhhc1 facilitates the nuclear translocation of p110α in macrophages, leading to a significant reduction in the downstream phosphorylation of Akt at Ser473 and mTOR at Ser2448. This cascade results in a decreased number of macrophages within plaques and ultimately mitigates the severity of atherosclerosis. These findings unveil a novel role for zDHHC1 in regulating foam cell formation and the progression of atherosclerosis, suggesting it as a promising target for clinical intervention in atherosclerosis therapy.

01 Sep 2024·Cell Reports

Zdhhc1- and Zdhhc2-mediated Gpm6a palmitoylation is essential for maintenance of mammary stem cell activity

Article

Author: Wu, Gaosong ; Wei, Wei ; Guo, Luyao ; Chen, Weizhen ; Cai, Cheguo

Adult mammary stem cells (aMaSCs) are vital to tissue expansion and remodeling during the process of postnatal mammary development. The protein C receptor (Procr) is one of the well-identified surface markers of multipotent aMaSCs. However, an understanding of the regulatory mechanisms governing Procr's protein stability remains incomplete. In this study, we identified Glycoprotein m6a (Gpm6a) as a critical protein for aMaSC activity modulation by using the Gpm6a knockout mouse model. Interestingly, we determined that Gpm6a depletion results in a reduction of Procr protein stability. Mechanistically, Gpm6a regulates Procr protein stability by mediating the formation of lipid rafts, a process requiring Zdhhc1 and Zdhhc2 to palmitate Gpm6a at Cys^17,18 and Cys²⁴⁶ sites. Our findings highlight an important mechanism involving Zdhhc1- and Zdhhc2-mediated Gpm6a palmitoylation for the regulation of Procr stability, aMaSC activity, and postnatal mammary development.

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ZDHHC1

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