Regulation and function of the palmitoyl‐acyltransferase ZDHHC5

Abstract

Protein palmitoylation (S-acylation) has emerged as an important player in a range of cellular processes, and as a result, the palmitoyl-acyltransferase (PAT) enzymes which mediate this modification have entered into the spotlight. Palmitoyltransferase ZDHHC5 (ZDHHC5) is among the more unique members of the PAT family as it is mainly localised to the plasma membrane and contains an extended cytoplasmic domain with several regulatory features. ZDHHC5 plays a vital role in a wide range of processes in different cell types. In this review, we offer a summary of the functions of ZDHHC5 in synaptic plasticity, cardiac function, cell adhesion and fatty acid uptake, among other processes. We also explore recent work has revealed several mechanisms to control the activity, localisation and function of ZDHHC5.

The interactions of ZDHHC5/GOLGA7 with SARS-CoV-2 spike (S) protein and their effects on S protein’s subcellular localization, palmitoylation and pseudovirus entry

“…S protein still interacted with the two mutants of ZDHHC5 including ZDHHC5-C134S or ZDHHC5△PDZ, indicating that the interaction between S protein and ZDHHC5 was independent of the enzymatic activity and the PDZ-binding domain of ZDHHC5. ZDHHC5 usually interacts with substrate proteins through its own PDZ binding domain and its DHHC motif also affects its interactions with substrate proteins [ 17 , 18 ]. These implied that ZDHHC5 might interact with different substrate proteins via different binding sites.…”

“…Probably because ZDHHC5 knockout could affect the palmitoylation of S protein at earlier infected stage, which led to the decrease of the pseudovirus entry efficiency, suggesting that the palmitoylation of S protein at later infected stages is catalyzed by other palmitoyltransferase members. Moreover, the ZDHHC5 knockout likely affects the functions of other cognate substrates, such as nucleotide oligomerization domain (NOD)-like receptors 1 and 2 (NOD1/2) which are involved in infecting of SARS-CoV-2, to decrease the entry efficiency of pseudovirus [ 17 , 18 ]. As previously reported, NOD1 is required for recognition of SARS-CoV-2 in lung epithelial cells [ 29 ].…”

“…ZDHHC5 can palmitoylate many protein substrates and participate in some important physiological processes, such as fatty acid uptake and immune response [ 16 , 17 ]. ZDHHC5 usually interacts with substrate proteins through its own PDZ (PSD-95/Discs-large/ZO-1 homology) binding domain and substitution of the cysteine residue in DHHC motif by a serine residue leads to enzyme inactivation [ 18 ]. However, the palmitoylated cysteine residues of S protein, the effects of ZDHHC5 or GOLGA7 knockout on S protein’s subcellular localization, palmitoylation, pseudovirus entry, and the enzyme for depalmitoylation of S protein are not clear.…”

Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo

“…Regulation of compartmentalized PMP functions might also be acutely regulated by controlling the action of PATs locally. This seems true for zDHHC5, as recent studies point to an intricated regulation of its activity and localization by posttranslational modifications and accessory proteins (see below) 43,54 .…”

ZDHHC5 targets Protocadherin 7 to the cell surface by a palmitoylation-dependent mechanism to promote successful cytokinesis

“…In contrast to the majority of PAT members that localize to Golgi or endoplasmic reticulum, ZDHHC5 localizes in the plasma membrane (Ohno et al, 2006). ZDHHC5 has been implicated in multiple cellular processes such as endocytosis, cell adhesion, Na-pump activity, and pathogen-host interaction partly by regulating the localization of related proteins (Plain et al, 2020; Pradhan et al, 2021; Woodley and Collins, 2019, 2021). In this study for the first time, we analyzed the function of ZDHHC5 in the context of cell division.…”