Noncanonical NF-κB Signaling in Health and Disease.

Noncanonical NF-κB signaling differs from canonical NF-κB signaling by being activated through different cell surface receptors, cytoplasmic adaptors, and NF-κB dimers. Under normal physiological conditions, this noncanonical pathway has been implicated in diverse biological processes, including lymphoid organogenesis, B cell maturation, osteoclast differentiation, and various functions of other immune cells. Recently, dysfunction of this pathway has also been causally associated with numerous immune-mediated pathologies and human malignancies. Here, we summarize the core elements as well as the recently identified novel regulators of the noncanonical NF-κB signaling pathway. The involvement of this pathway in different pathologies and the potential therapeutic options that are currently envisaged are also discussed.

Quantitative assessment of telomerase components in cancer cell lines.

Besides its canonical function of catalyzing the formation of telomeric repeats, many groups have recently reported non-canonical functions of hTERT in particular, and telomerase in general. Regulating transcription is the central basis of non-canonical functions of telomerase. However, unlike reverse transcriptase activity of telomerase that requires only a few molecules of enzymatically active hTERT, non-canonical functions of hTERT or other telomerase components theoretically require several hundred copies. Here, we provide the first direct quantification of all the telomerase components in human cancer cell lines. We demonstrate that telomerase components do not exist in a 1:1 stoichiometric ratio, and there are several hundred copies of hTERT in cells. This provides the molecular basis of hTERT to function in other signaling cascades, including transcription.

Telomerase: central regulator of all of the hallmarks of cancer.

The hallmarks of cancer described by Hanahan and Weinberg are properties that cancer cells must possess for successful transformation. It is believed that each of these hallmarks is independently driven. Although elongation of telomeres is thought to be the prime function of reactivated telomerase reverse transcriptase, this activity does not account for all its effects, such as increasing cell proliferation, resistance to apoptosis, and invasion. Recent studies suggest that the telomerase subunit telomerase reverse transcriptase (TERT) has novel molecular functions including transcriptional regulation and metabolic reprogramming. We summarize these functions and discuss how they could directly regulate the various hallmarks of cancer. Finally, we suggest that therapeutics targeting noncanonical telomerase functions may work better than those that target its role in telomere extension.

Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria.

Individuals with type 2 diabetes are at increased risk of acquiring melioidosis, a disease caused by Burkholderia pseudomallei infection. Although up to half of melioidosis patients have underlying diabetes, the mechanisms involved in this increased susceptibility are unknown. We found that B. pseudomallei-infected PBMCs from diabetic patients were impaired in IL-12p70 production, which resulted in decreased IFN-γ induction and poor bacterial killing. The defect was specific to the IL-12-IFN-γ axis. Defective IL-12 production was also observed during Mycobacterium tuberculosis infection, in which diabetes is likewise known to be a strong risk factor. In contrast, IL-12 production in diabetic cells was not affected upon Salmonella enterica infection or in response to TLR2, -3, -4, and -5 ligands. Poor IL-12 production correlated with a deficiency in intracellular reduced glutathione (GSH) concentrations in diabetic patients. Addition of GSH or N-acetylcysteine to PBMCs selectively restored IL-12 and IFN-γ production and improved bacterial killing. Furthermore, the depletion of GSH in mice led to increased susceptibility to melioidosis, reduced production of IL-12p70, and poorer disease outcome. Our data thus establish a link between GSH deficiency in diabetes and increased susceptibility to melioidosis that may open up new therapeutic avenues to protect diabetic patients against some intracellular bacterial pathogens.