Two splicing factors carrying serine-arginine motifs, TSR1 and TSR1IP, regulate splicing, mRNA stability, and rRNA processing in Trypanosoma brucei
RNA BIOLOGY
Authors: Gupta, Sachin Kumar; Chikne, Vaibhav; Eliaz, Dror; Tkacz, Itai Dov; Naboishchikov, Ilana; Carmi, Shai; Ben-Asher, Hiba Waldman; Michaeli, Shulamit
Abstract
In trypanosomes, mRNAs are processed by trans-splicing; in this process, a common exon, the spliced leader, is added to all mRNAs from a small RNA donor, the spliced leader RNA (SL RNA). However, little is known regarding how this process is regulated. In this study, we investigated the function of two serine-arginine-rich proteins, TSR1 and TSR1IP, implicated in trans-splicing in Trypanosoma brucei. Depletion of these factors by RNAi suggested their role in both cis- and trans-splicing. Microarray was used to examine the transcriptome of the silenced cells. The level of hundreds of mRNAs was changed, suggesting that these proteins have a role in regulating only a subset of T. brucei mRNAs. Mass-spectrometry analyses of complexes associated with these proteins suggest that these factors function in mRNA stability, translation, and rRNA processing. We further demonstrate changes in the stability of mRNA as a result of depletion of the two TSR proteins. In addition, rRNA defects were observed under the depletion of U2AF35, TSR1, and TSR1IP, but not SF1, suggesting involvement of SR proteins in rRNA processing.
Alpha2delta-1 in SF1(+) Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis
CELL REPORTS
Authors: Felsted, Jennifer A.; Chien, Cheng-Hao; Wang, Dongqing; Panessiti, Micaella; Ameroso, Dominique; Greenberg, Andrew; Feng, Guoping; Kong, Dong; Rios, Maribel
Abstract
The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that alpha 2 delta-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus (VMH). These effects are body weight independent and involve regulation of SF1(+) neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with alpha 2 delta-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation. Profound reductions in the firing rate of SF1 neurons, decreased sympathetic output, and elevated circulating levels of serotonin are associated with these alterations. Normal calcium currents but reduced excitatory postsynaptic currents in mutant SF1 neurons implicate alpha 2 delta-1 in the promotion of excitatory synaptogenesis separate from its canonical role as a calcium channel subunit. Collectively, these findings identify an essential mechanism that regulates VMH neuronal activity and glycemic and lipid control and may be a target for tackling metabolic disease.
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