LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer.

NKX3.1's downregulation is strongly associated with prostate cancer (PCa) initiation, progression, and CRPC development. Nevertheless, a clear disagreement exists between NKX3.1 protein and mRNA levels in PCa tissues, indicating that its regulation at a post-translational level plays a vital role. This study identified a strong negative relationship between NKX3.1 and LIMK2, which is critical in CRPC pathogenesis. We identified that NKX3.1 degradation by direct phosphorylation by LIMK2 is crucial for promoting oncogenicity in CRPC cells and in vivo. LIMK2 also downregulates NKX3.1 mRNA levels. In return, NKX3.1 promotes LIMK2's ubiquitylation. Thus, the negative crosstalk between LIMK2-NKX3.1 regulates AR, ARv7, and AKT signaling, promoting aggressive phenotypes. We also provide a new link between NKX3.1 and PTEN, both of which are downregulated by LIMK2. PTEN loss is strongly linked with NKX3.1 downregulation. As NKX3.1 is a prostate-specific tumor suppressor, preserving its levels by LIMK2 inhibition provides a tremendous opportunity for developing targeted therapy in CRPC. Further, as NKX3.1 downregulates AR transcription and inhibits AKT signaling, restoring its levels by inhibiting LIMK2 is expected to be especially beneficial by co-targeting two driver pathways in tandem, a highly desirable requisite for developing effective PCa therapeutics.

Interrupting cyclic dinucleotide-cGAS-STING axis with small molecules.

The cyclic dinucleotide-cGAS-STING axis plays important roles in host immunity. Activation of this signaling pathway, via cytosolic sensing of bacterial-derived c-di-GMP/c-di-AMP or host-derived cGAMP, leads to the production of inflammatory interferons and cytokines that help resolve infection. Small molecule activators of the cGAS-STING axis have the potential to augment immune response against various pathogens or cancer. The aberrant activation of this pathway, due to gain-of-function mutations in any of the proteins that are part of the signaling axis, could lead to various autoimmune diseases. Inhibiting various nodes of the cGAS-STING axis could provide relief to patients with autoimmune diseases. Many excellent reviews on the cGAS-STING axis have been published recently, and these have mainly focused on the molecular details of the cGAS-STING pathway. This review however focuses on small molecules that can be used to modulate various aspects of the cGAS-STING pathway, as well as other parallel inflammatory pathways.

Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-ß levels.

AIM: Persistent activation of STING pathway is the basis for several autoimmune diseases. STING is activated by cGAMP, which is produced by cGAS in the presence of DNA. Results/methodology: HPLC-based medium throughput screening for inhibitors of cGAS identified suramin as a potent inhibitor. Unlike other reported cGAS inhibitors, which bind to the ATP/GTP binding site, suramin displaced the bound DNA from cGAS. Addition of suramin to THP1 cells reduced the levels of IFN-ß mRNA and protein. Suramin did not inhibit lipopolysaccharide- or Pam3CSK4-induced IL-6 mRNA expression. CONCLUSION: Suramin inhibits STING pathway via the inhibition of cGAS enzymatic activity. Suramin or analogs thereof that displace DNA from cGAS could be used as anti-inflammatory drugs.

Outer membrane protein biogenesis in Gram-negative bacteria.

Gram-negative bacteria contain a double membrane which serves for both protection and for providing nutrients for viability. The outermost of these membranes is called the outer membrane (OM), and it contains a host of fully integrated membrane proteins which serve essential functions for the cell, including nutrient uptake, cell adhesion, cell signalling and waste export. For pathogenic strains, many of these outer membrane proteins (OMPs) also serve as virulence factors for nutrient scavenging and evasion of host defence mechanisms. OMPs are unique membrane proteins in that they have a ß-barrel fold and can range in size from 8 to 26 strands, yet can still serve many different functions for the cell. Despite their essential roles in cell survival and virulence, the exact mechanism for the biogenesis of these OMPs into the OM has remained largely unknown. However, the past decade has witnessed significant progress towards unravelling the pathways and mechanisms necessary for moulding a nascent polypeptide into a functional OMP within the OM. Here, we will review some of these recent discoveries that have advanced our understanding of the biogenesis of OMPs in Gram-negative bacteria, starting with synthesis in the cytoplasm to folding and insertion into the OM.