Regulation of StAR by the N-terminal Domain and Coinduction of SIK1 and TIS11b/Znf36l1 in Single Cells

The cholesterol transfer function of StAR is uniquely integrated into adrenal cells, with mRNA translation and PKA phosphorylation occurring at the mitochondrial outer membrane (OMM). The StAR C-terminal cholesterol binding domain (CBD) initiates mitochondrial inter-membrane contacts to rapidly direct cholesterol to Cyp11a1 in the inner membrane (IMM). The conserved StAR N-terminal regulatory domain (NTD) includes a leader sequence targeting the CBD to OMM complexes that initiate cholesterol transfer. Here we show how the NTD functions to enhance CBD activity delivers more efficiently from StAR mRNA in adrenal cells and then how two factors hormonally restrain this process. NTD processing at two conserved sequence sites is selectively affected by StAR PKA phosphorylation. The CBD functions as a receptor to stimulate the OMM/IMM contacts that mediate transfer. The NTD controls the transit time that integrates extra-mitochondrial StAR effects on cholesterol homeostasis with other mitochondrial functions, including ATP generation, inter-organelle fusion and the major permeability transition pore in partnership with other OMM proteins. PKA also rapidly induces two additional StAR modulators: SIK1 and Znf36l1/Tis11b. Induced SIK1 attenuates the activity of CRTC2, a key mediator of StAR transcription and splicing, but only as cAMP levels decline. TIS11b inhibits translation and directs the endonuclease-mediated removal of the 3.5-kb StAR mRNA. Removal of either of these functions individually enhances cAMP-mediated induction of StAR. High-resolution fluorescence in situ hybridization (HR-FISH) of StAR RNA reveals asymmetric transcription at the gene locus and slow RNA splicing that delays mRNA formation, potentially to synchronize with cholesterol import. Adrenal cells may retain slow transcription to integrate with intermembrane NTD activation. HR-FISH resolves individual 3.5-kb StAR mRNA molecules via dual hybridization at the 3’- and 5’ ends and reveals an unexpectedly high frequency of 1:1 pairing with mitochondria marked by the matrix StAR protein. This pairing may be central to translation-coupled cholesterol transfer. Altogether, our results show that adrenal cells exhibit high- efficiency StAR activity that needs to integrate rapid cholesterol transfer with homeostasis and pulsatile hormonal stimulation. StAR NBD, the extended 3.5kb mRNA, SIK1, and Tis11b play important roles

Melioidosis in Singapore: Clinical, Veterinary, and Environmental Perspectives

Melioidosis is a notifiable infectious disease registered with the Ministry of Health (MOH) and Agri-Food & Veterinary Authority (AVA), Singapore. From a clinical perspective, increased awareness of the disease has led to early detection and treatment initiation, thus resulting in decreasing mortality rates in recent years. However, the disease still poses a threat to local pet, zoo and farm animals, where early diagnosis is a challenge. The lack of routine environmental surveillance studies also makes prevention of the disease in animals difficult. To date, there have been no reports that provide a complete picture of how the disease impacts the local human and animal populations in Singapore. Information on the distribution of Burkholderia pseudomallei in the environment is also lacking. The aim of this review is to provide a comprehensive overview of both published and unpublished clinical, veterinary and environmental studies on melioidosis in Singapore to achieve better awareness and management of the disease