Bacterial trans translation is activated when translating ribosomes are unable to elongate or terminate properly. Small protein B (SmpB) and transfer-messenger RNA (tmRNA) are the two known factors required for and dedicated to trans translation. tmRNA, encoded by the ssrA gene, is a bifunctional molecule that acts both as a tRNA and as an mRNA during trans translation. The functions of tmRNA ensure that stalled ribosomes are rescued, the causative defective mRNAs are degraded, and the incomplete polypeptides are marked for targeted proteolysis. We present in vivo and in vitro evidence that demonstrates a direct role for the Lon ATP-dependent protease in the degradation of tmRNA-tagged proteins. In an endogenous protein tagging assay, lon mutants accumulated excessive levels of tmRNA-tagged proteins. In a reporter protein tagging assay with -CI-N, the protein product of a nonstop mRNA construct designed to activate trans translation, lon mutant cells efficiently tagged the reporter protein, but the tagged protein exhibited increased stability. Similarly, a green fluorescent protein (GFP) construct containing a hard-coded C-terminal tmRNA tag (GFP-SsrA) exhibited increased stability in lon mutant cells. Most significantly, highly purified Lon preferentially degraded the tmRNA-tagged forms of proteins compared to the untagged forms. Based on these results, we conclude that Lon protease participates directly in the degradation of tmRNA-tagged proteins.
It is widely accepted that acute demyelinating plaques in patients with multiple sclerosis (MS) demonstrate increased apparent diffusion coefficient (ADC) and increased diffusion weighted imaging (DWI) signals on MRI. These imaging characteristics in acute MS lesions have been postulated to be due to peripheral vasogenic edema that typically increases the apparent diffusion coefficient (ADC). This assumption is commonly used to differentiate stroke from MS lesions since acute and subacute stroke lesions demonstrate increased DWI signal with reduced ADC due to acute cytotoxic edema.We report a case of active relapsing-remitting MS with two new symptomatic contrast-enhancing lesions. The lesions had reduced diffusion on the ADC map in the early acute phase of MS exacerbation. The reduced ADC signal was subsequently "converted" to increased ADC signal which coincided with the development of profound peripheral vasogenic edema seen on T2-weighted images. To our knowledge, this is the first serial MRI study describing decreased ADC signal in the early acute phase of contrast-enhancing MS lesion. The implications of decreased diffusion in the acute phase of MS lesions for the disease pathogenesis are discussed.
Background/Objective-Viral infections have been implicated in the pathogenesis of multiple sclerosis (MS). Plasmacytoid dendritic cells (pDCs) are present in peripheral blood, cerebrospinal fluid and brain lesions of MS patients. PDCs sense viral DNA via Toll-like receptor 9 (TLR9) which has to be cleaved from the N-terminal to become functional (TLR9 processing). PDCs activated with TLR9 agonists promote Th1/Th17-responses. In the animal model of MS, TLR9 agonists can induce disease. We hypothesized that pDCs are inhibited by disease-modifying therapy such as IFN-beta, consequently decreasing the frequency of MS attacks.
Background MS is an immune-mediated inflammatory disease of the CNS. B cells have been strongly implicated in disease pathogenesis based on clinical trials with B cell ablation. There is a growing body of evidence linking microRNAs with regulation of the immune system. Dicer, a key enzyme involved in microRNA biogenesis, is necessary for normal B cell function. Objective To determine whether Dicer expression is impaired in B cells and is linked to increased expression co-stimulatory molecules in MS patients. Methods B cells were separated from MS patients and healthy subjects. Expression of Dicer and co-stimulatory molecules CD80 and CD86 was tested. The effect of Dicer modulation on CD80 and CD86 expression in B cells was studied. Results Dicer expression was decreased in B cells but not in monocytes of MS patients compared to healthy subjects. CD80 and CD86 expression was increased on B cells of MS patients compared to healthy subjects. Inhibition of Dicer expression in B cells by small interfering RNA led to increased expression of CD80. Conclusion Dicer expression is decreased and is mechanistically linked to increased expression of co-stimulatory molecule CD80 in B cells of MS patients. This may contribute to activation of immune responses in MS.
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