DHHC7 Palmitoylates Glucose Transporter 4 (Glut4) and Regulates Glut4 Membrane Translocation

Abstract

Insulin-dependent translocation of glucose transporter 4 (Glut4) to the plasma membrane plays a key role in the dynamic regulation of glucose homeostasis. We recently showed that this process is critically dependent on palmitoylation of Glut4 at Cys-223. To gain further insights into the regulation of Glut4 palmitoylation, we set out to identify the palmitoyl acyltransferase (PAT) involved. Here we report that among 23 mammalian DHHC proteins, DHHC7 is the major Glut4 PAT, based on evidence that ectopic expression of DHHC7 increased Glut4 palmitoylation, whereas DHHC7 knockdown in 3T3-L1 adipocytes and DHHC7 KO in adipose tissue and muscle decreased Glut4 palmitoylation. Moreover, inactivation of DHHC7 suppressed insulin-dependent Glut4 membrane translocation in both 3T3-L1 adipocytes and primary adipocytes. Finally, DHHC7 KO mice developed hyperglycemia and glucose intolerance, thereby confirming that DHHC7 represents the principal PAT for Glut4 and that this mechanism is essential for insulin-regulated glucose homeostasis.

The Absence of DHHC3 Affects Primary and Latent Herpes Simplex Virus 1 Infection

“…In contrast, we previously reported an at least 3-logunit reduction in virus infectivity in mutant viruses lacking UL20 or gK (2)(3)(4)(29)(30)(31)(32). We previously showed that GODZ and its most closely related paralog, SERZ-␤, have indistinguishable substrate specificities in vitro; in contrast, in vivo, the two enzymes have distinct distributions in the Golgi complex (19,49). While GODZ is highly restricted to the cis-Golgi network, SERZ-␤ is preferentially localized to the trans-Golgi network, and our previous results pointed to partial functional redundancy of GODZ and SERZ-␤ (19,49).…”

“…We previously showed that GODZ and its most closely related paralog, SERZ-␤, have indistinguishable substrate specificities in vitro; in contrast, in vivo, the two enzymes have distinct distributions in the Golgi complex (19,49). While GODZ is highly restricted to the cis-Golgi network, SERZ-␤ is preferentially localized to the trans-Golgi network, and our previous results pointed to partial functional redundancy of GODZ and SERZ-␤ (19,49). Thus, the smaller defects in virus replication seen in GODZ Ϫ/Ϫ cells than in experiments testing mutant viruses are likely due to compensation for loss of GODZ function by SERZ-␤.…”

DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels

“…A multitude of DHHC proteins exists in eukaryotic cells, including 8 in yeast (11), (12) and 23 in humans (13). Various studies, including our own, indicate that DHHC proteins possess distinct but overlapping substrate specificities (14), (15), (16). As palmitoylation controls a variety of important cellular processes, it is not surprising that several DHHC proteins are implicated in human disease (17), (18), (19), (20), (21).…”

Binding of Herpes Simplex Virus 1 UL20 to GODZ (DHHC3) Affects Its Palmitoylation and Is Essential for Infectivity and Proper Targeting and Localization of UL20 and Glycoprotein K

“…Palmitoyl transferases with this DHHC configuration are present in all eukaryotes and occur as multienzyme families that range in size from 5 to 24 members (16,17). They play multiple critical roles in physiology and a variety of diseases, including cancer, Huntington's disease, and X-linked intellectual disability (18)(19)(20)(21)(22). GODZ is highly conserved between humans, mice, rats, fruit flies, and Caenorhabditis elegans, with 97% homology between humans and mice (23).…”