Chang Xie

The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted syndrome in humans. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive therapeutics for skin inflammation.

Most mammalian cells take up cholesterol from low-density lipoproteins (LDLs) via receptor-mediated endocytosis. After reaching lysosomes, LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs. Peroxisomes are recently found to receive cholesterol from lysosomes through lysosome-peroxisome membrane contacts. However, whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown. Here, by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes, we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P₂ and ER-resident extended synaptotagmin-1, 2 and 3 (E-Syts). Depletion of peroxisomal PI(4,5)P₂ or E-Syts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes. Furthermore, we show that cholesterol is delivered from ³H-labeled peroxisomes or PI(4,5)P₂-containing liposomes to the ER in vitro, and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER. Together, our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.

Metabolism in mammals is regulated by complex interplay among different organs. Fatty acid synthesis is increased in white adipose tissue (WAT) when it is inhibited in the liver. Here we identify glycoprotein non-metastatic melanoma protein B (Gpnmb) as one liver–WAT cross-talk factor involved in lipogenesis. Inhibition of the hepatic sterol regulatory element-binding protein pathway leads to increased transcription of Gpnmb and promotes processing of the membrane protein to a secreted form. Gpnmb stimulates lipogenesis in WAT and exacerbates diet-induced obesity and insulin resistance. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver-specific knockdown improves metabolic parameters, including weight gain reduction and increased insulin sensitivity, probably by promoting the beiging of WAT. These results suggest that Gpnmb is a liver-secreted factor regulating lipogenesis in WAT, and that Gpnmb inhibition may provide a therapeutic strategy in obesity and diabetes.

Cardiac sodium channel plays a key role in the fast depolarization and maintenance of impulse conduction in cardiomyocytes. Mutations of SCN5A gene can lead to many types of arrhythmias. A 14-year-old boy with familial paternal history of sudden unexpected nocturnal death was admitted to hospital with recurrent syncope. A cardiac channelopathy was suspected and a pathogenic ion channel was searched for mutation identification. The proband manifested sinus node dysfunction, ventricular tachycardia, cardiac conduction disturbance involving atrioventricular node and His bundle. The proband and his mother received whole exome sequencing. A heterozygous in-frame deletion N1380del on exon 23 of SCN5A gene locating in a highly conserved pore residue in domain III (S5-S6) was revealed in the proband. The mutation was assessed in other family members by Sanger sequencing. The proband's living uncle and two sisters were asymptomatic mutation carriers with different degrees of cardiac conduction disturbance. Functional analysis was conducted using whole-cell patch clamping in HEK293T cells transfected with wild-type or mutant channels. The HEK293T cells transfected with plasmid pcDNA3.1-N1380del-SCN5A had no detectable sodium current. Overall, N1380del mutation of SCN5A gene leads to loss of function of sodium channel. N1380del is a pathogenetic mutation which can cause cardiac conduction defect and ventricular tachycardia.

Cell death and differentiation is a monthly research journal focused on the exciting field of programmed cell death and apoptosis. It provides a single accessible source of information for both scientists and clinicians, keeping them up-to-date with advances in the field. It encompasses programmed cell death, cell death induced by toxic agents, differentiation and the interrelation of these with cell proliferation.

This paper is to assess the current status of polybrominated diphenyl ethers (PBDEs) contamination in the environment in China and estimate the exposure to PBDEs in non-occupational populations.