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Background:The substrates and regulation of DHHC protein palmitoyl acyltransferases (PATs) are largely unknown. Results: Flotillin-2 palmitoylation is abolished in DHHC5 gene-targeted neural stem cells, and neuronal differentiation induces DHHC5 turnover. Conclusion: Flotillin-2 is a substrate for DHHC5, which is regulated at the protein level. Significance: The paper describes an approach to PAT substrate identification and a new PAT regulation mechanism.

Cytosolic HSP90 requires multiple cochaperones in folding client proteins. However, the function of gp96 (HSP90b1, grp94), an HSP90 paralogue in the endoplasmic reticulum (ER), is believed to be independent of cochaperones. Here, we demonstrate that gp96 chaperones multiple Toll-like receptors (TLRs), but not TLR3, in a manner that is dependent on another ER luminal protein, CNPY3. gp96 directly interacts with CNPY3, and the complex dissociates in the presence of adenosine triphosphate (ATP). Genetic disruption of gp96–CNPY3 interaction completely abolishes their TLR chaperone function. Moreover, we demonstrate that TLR9 forms a multimolecular complex with gp96 and CNPY3, and the binding of TLR9 to either molecule requires the presence of the other. We suggest that CNPY3 interacts with the ATP-sensitive conformation of gp96 to promote substrate loading. Our study has thus established CNPY3 as a TLR-specific cochaperone for gp96.

Background: Prophylactic human papillomavirus (HPV) vaccines are available, but uptake is suboptimal. Information on factors influencing parental decisions regarding vaccination will facilitate the development of successful interventions.Methods: Parents of girls ages 9 to 17 years (n = 476; cooperation rate = 67%) from a panel of U.S. households completed online surveys between September 2007 and January 2008, documenting vaccine knowledge, attitudes, and intentions.Results: Among those aware of the vaccine, 19% had already vaccinated their daughter(s), 34% intended to, 24% were undecided, and 24% had decided against vaccination. Awareness of HPV was high but knowledge levels were suboptimal (mean 72%, SEM 0.8%). Black and Hispanic parents were significantly less likely to be aware of the vaccine compared with White parents. In multivariate analyses, compared with parents who opposed vaccination, those who had already vaccinated their daughter(s) or who intended to do so had more positive attitudes, reported fewer barriers, and were more likely to perceive that family and friends would endorse vaccination. They also reported higher levels of trust in pharmaceutical companies that produce the vaccine.Conclusions: Despite limited knowledge, most parents had decided to vaccinate their daughter(s). Given evidence of diminished access to information among Black and Hispanic parents, programs should focus on reaching these groups. Interventions should address parental concerns about behavioral consequences, reduce structural barriers, and promote the perception that vaccination is endorsed by significant others. Moreover, interventions may need to address mistrust of pharmaceutical companies.Impact Statement: This study documents factors associated with parental decisions about HPV vaccination for their daughter(s) and provides direction for intervention development. Cancer Epidemiol Biomarkers Prev; 19

A family of integral membrane proteins containing a signature DHHC motif has been shown to display protein S-acyltransferase activity, modifying cysteine residues in proteins with fatty acids. The physiological roles of these proteins have largely been unexplored. Here we report that mice homozygous for a hypomorphic allele of a previously uncharacterized member, DHHC5, are born at half the expected rate, and survivors show a marked deficit in contextual fear conditioning, an indicator of defective hippocampal-dependent learning. DHHC5 is highly enriched in a post-synaptic density preparation and co-immunoprecipitates with post-synaptic density protein-95 (PSD-95), an interaction that is mediated through binding of the carboxyl terminus of DHHC5 and the PDZ3 domain of PSD-95. Immunohistochemistry demonstrated that DHHC5 is expressed in the CA3 and dentate gyrus in the hippocampus. These findings point to a previously unsuspected role for DHHC5 in post-synaptic function affecting learning and memory.Palmitoylation of proteins at intracellular sites is mediated by members of a family of S-fatty acyltransferases that are recognized by a DHHC consensus motif at the active site (1-4). In addition to functioning as protein S-acyltransferases, other functions have been proposed, with certain family members shown to transport divalent cations (5-6). The roles of DHHC proteins in the nervous system have attracted recent interest. Genetic alterations in DHHC9 and DHHC15 are responsible for two different forms of X-linked mental retardation in humans (7-9), whereas DHHC8 is contained within a microdeletion linked to schizophrenia in the Han Chinese population (10), and DHHC17 interacts with huntingtin (Htt) and may play a role in the pathogenesis of Huntington disease (11-13). Another DHHC family member, GODZ (DHHC3), has been shown to affect both excitatory and inhibitory synapse function (14 -19), and DHHC23 (neuronal nitric oxide synthetase (nNOS) 2 -interacting DHHC domain-containing protein with dendritic mRNA (NIDD)) targets neuronal nitric oxide synthetase to synapses via its nNOS PDZ binding domain (20). Given the large number of family members (22 in human and 23 in mouse) and the daunting number of potential substrates (over 250 in the brain, for example) (21), mouse models will become increasingly important for understanding their physiological roles. Of note, the only previously available DHHC gene knock-out mouse model (the DHHC8 model (22)), exhibits behavioral abnormalities and defects in neuronal culture (such as diminished density of dendritic spines) (23).In this study we show that a previously uncharacterized DHHC family member, DHHC5, is highly enriched in the brain and in synaptic vesicle fractions and that it interacts with the third PDZ binding domain of PSD-95 in vitro and in vivo. Mice homozygous for a hypomorphic allele of DHHC5 show impaired contextual fear conditioning. DHHC5 is shown to contain a hydroxylamine-sensitive acyl group in vivo, but PSD-95 palmitoylation is unchanged in DHHC5 knock-o...

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Labor union apprenticeship programs represent a promising venue for smoking cessation interventions, particularly those that draw upon a health promotion-health protection model.