Objective Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is an autoinflammatory syndrome recently described in children. We investigated the clinical phenotype, genetic cause and the immune dysregulation in nine CANDLE patients. Methods Genomic DNA from all patients was screened for PSMB8 (Proteasome subunit beta type-8) mutations. Serum cytokine levels were measured from four patients. Skin biopsies were evaluated immunohistochemically and blood microarray profile (n=4) and stat-1 phosphorylation (n=3) were assessed. Results One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A) suggesting a protein truncation, four patients were homozygous and two were heterozygous for a previously reported missense mutation (c.224C>T), and one patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the four patients with the same mutation, only two share the same haplotype indicating a mutational hot spot. PSMB8 mutation-positive and -negative patients expressed high IP-10 (Interferon gamma-induced protein 10) levels. Levels of MCP-1, IL-6, and IL-1Ra were moderately elevated. Microarray profiles and monocyte stat-1 activation suggested a unique interferon (IFN) signaling signature, unlike in other autoinflammatory disorders. Conclusion CANDLE is caused by mutations in PSMB8, a gene recently reported to cause JMP syndrome (joint contractures, muscle atrophy and panniculitis induced lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8-associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target.

Phytochromes are well-known red/far-red photosensory proteins that utilize the photoisomerization of a linear tetrapyrrole (bilin) chromophore to detect the ratio of red to far-red light. Cyanobacteriochromes (CBCRs) are related photosensory proteins with a bilin-binding GAF domain, but much more diverse spectral sensitivity, with five recognized subfamilies of CBCRs described to date. The mechanisms that underlie this spectral diversity have not yet been fully elucidated. One of the main CBCR subfamilies photoconverts between a red-absorbing ground state, like the familiar P(r) state of phytochromes, and a green-absorbing photoproduct (P(g)). Here, we examine the ultrafast forward photodynamics of the red/green CBCR NpR6012g4 from the NpR6012 locus of the nitrogen-fixing cyanobacterium Nostoc punctiforme. Using transient absorption spectroscopy with broadband detection and multicomponent global analysis, we observed multiphasic excited-state dynamics that induces the forward reaction (red-absorbing to green-absorbing), which we interpret as arising from ground-state heterogeneity. Excited-state decays with lifetimes of 55 and 345 ps generate the primary photoproduct (Lumi-R), and the fastest decay (5 ps) did not produce Lumi-R. Although the photoinduced kinetics of Npr6012g4 is comparable with that of the Cph1 phytochrome isolated from Synechocystis cyanobacteria, NpR6012g4 exhibits a ≥2-3-fold higher photochemical quantum yield. Understanding the structural basis of this enhanced quantum yield may prove to be useful in increasing the photochemical efficiency of other bilin-based photosensors.

The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. These interactions require zinc and are critical for T cell development and activation. We examined the folding and solution structures of ternary CD4-Lck-Zn2+ and CD8alpha-Lck-Zn2+ complexes. The coreceptor tails and the Lck N-terminus are unstructured in isolation but assemble in the presence of zinc to form compactly folded heterodimeric domains. The cofolded complexes have similar "zinc clasp" cores that are augmented by distinct structural elements. A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck.