Research highlights

In this issue of The FEBS Journal, we highlight a study by Tuhkanen et al. that explores how single-nucleotide polymorphisms can affect β1AR receptor processing and function, and a report by Riccuiti and colleagues investigating how a bacterial chemoreceptor associated with chemotaxis actually promotes biofilm formation. We also feature work by Yang and co-authors exploring the role of cholesterol in inflammatory bowel disease, and last but not least, a study by Schmidt and team demonstrating the challenges of targeting a signalling pathway regulated by feedback inhibition. Image created using Wordclouds.com. The β1-adrenergic receptor (β1AR) binds adrenaline and noradrenaline to activate pathways that play important roles in regulating cardiac function. During heart failure, prolonged activation of β1AR can cause its desensitisation and downregulation, eventually leading to chronic cardiac dysfunction. β-adrenergic antagonists, commonly known as β-blockers, overcome this by ‘blocking’ this constitutive signalling. However, treatment responses to β-blockers vary, and this has been partly attributed to the occurrence of single-nucleotide polymorphisms (SNPs) in the gene that encodes β1AR, ADRB1. While the common SNP R389G, affecting the C-terminal intracellular region of β1AR, has been previously reported to impact receptor activity, the functional implications of SNPs in the extracellular N-terminal domain are not well-understood. In this study, Tuhkanen and co-authors investigated the effects of N-terminal β1AR SNPs on receptor processing, function and signalling. They previously demonstrated that β1AR undergoes proteolytic cleavage and O-glycosylation, with an interplay between both coregulating downstream signalling. The authors found that the commonly occurring S49G SNP, and the rarer SNPs A29T and R31Q, could affect O-glycosylation and consequently influence site-specific proteolytic cleavage of β1AR. While A29T enhanced O-glycosylation and thus protected the receptor from cleavage, S49G eliminated an O-glycosite, thereby enhancing cleavage. The R31Q SNP protected β1AR from cleavage by removing a cleavage site completely. Consequently, A29T and R31Q SNPs lead to increased levels of the full-length receptor at the cell surface, whereas the converse is true for S49G. Beyond providing significant insight into the maturation and function of β1AR, this study highlights the importance of factoring in genetic backgrounds when prescribing treatments to patients, and emphasises how personalised medicine and coordinated bench-to-bedside and bedside-to-bench research can help inform new treatment strategies for patients and improve therapeutic responses. Bacterial survival heavily depends on the ability to sense changes in the surrounding chemical environment and adapt behaviour accordingly. The signal transduction systems that govern this ability, termed ‘chemosensing’, have been heavily studied. However, many questions such as the specific stimuli that trigger signalling of these pathways still remain unanswered. Here, Ricciuti and co-authors investigated the specificity of Htc10, a chemoreceptor in the marine bacterium H. titanicae KHS3. The genome of this bacterium contains two chemotaxis-related gene clusters. While one of these controls chemotaxis, the other cluster, HtChe2, does not impact chemotaxis and instead might have an alternative cellular function. Interestingly, Htc10 is the only chemoreceptor encoded within the HtChe2 gene cluster and is also structurally similar to WspA, which regulates biofilm formation in Pseudomonas. Furthermore, the structure of Htc10 suggests that it signals independently from the rest of the chemotaxis pathway. In this study, the authors focused on the ligand-binding domain of Htc10 and identified guanine and hypoxanthine as specific ligands for this chemoreceptor. When they expressed Htc10 in a Pseudomonas strain lacking the WspA receptor, this heterologous expression enhanced biofilm formation, which was further increased by the addition of Htc10's ligands, guanine and hypoxanthine. These results therefore confirm that Htc10 and WspA have similar functions in promoting biofilm formation. The authors speculate that the conservation of Htc10-like chemoreceptors across diverse bacteria suggests that the pathway has likely been maintained, or even actively incorporated, upon selection pressure. Htc10-like chemoreceptors might therefore play a critical role in the survival of the organisms they are found in. Inflammatory bowel disease (IBD) is characterised by chronic intestinal mucosal inflammation and a disruption of the intestinal barrier, and significantly impairs the quality of life of affected individuals. Effective treatment options remain limited, largely due to the mostly unknown pathogenesis of IBD. Although the exact disease aetiology is unclear, previous research has found a higher expression of cholesterol biosynthesis-associated genes in the intestinal tissues of IBD patients, suggesting a link between cholesterol metabolism and IBD. And while cholesterol is known to impact the development of cardiovascular diseases, the role it plays in IBD pathogenesis is yet to be understood. In this study, Yang and co-investigators explored the effects of a high-cholesterol diet in a mouse model with induced colitis. They found that the colons of high-cholesterol diet-fed mice with existing colitis exhibited more pathological damage—they had shorter colons and multiple ulcers compared to their counterparts on a ‘normal’ diet. They also found that the high-cholesterol diet disrupted the structure of tight junctions in the colonic epithelium of these mice, suggesting that cholesterol might play a role in epithelial barrier impairment. They explored the underlying mechanism and found that cholesterol treatment decreases the stability and expression of tight-junction proteins occludin and Zo-1, which are critical for maintenance of the intestinal epithelial barrier. Investigating the mechanism further, the authors demonstrated that colitis mice fed a high-cholesterol diet expressed lower levels of SREBP2, which increased the endocytic uptake and subsequent degradation of occludin and Zo-1. Interestingly, the authors also found that a single-nucleotide polymorphism in the gene encoding SREBP2 was associated with a lower incidence of IBD in a biobank cohort of patients. Carrying a ‘CC’ variant of this gene was associated not only with a reduced risk of IBD but also with a delayed development of incident IBD when compared to the ‘GG’ or ‘GC’ genotypes. The findings of this study provide new insights into the pathogenesis underlying IBD and how diet might affect the severity of the disease, and suggest that SREBP2 could be leveraged as a potential therapeutic target for IBD treatment. Loss of feedback regulation is a common mechanism underlying drug resistance across multiple cancer types. In this study, Schmidt and colleagues investigate AXIN2, a β-catenin transcriptional target and Wnt signalling negative feedback regulator, and its homologue, AXIN1. AXIN1/2 are also components of a β-catenin ‘destruction complex’, and can consequently inhibit Wnt signalling, which is commonly hyperactivated in colorectal and other cancer types. They found that while depletion of AXIN2 increased AXIN1 expression and stability, Wnt signalling could still be activated upon AXIN2 loss, suggesting that AXIN1 cannot compensate for AXIN2's regulatory role in this system. The authors used inhibitors to target tankyrase, which mediates the degradation of both AXIN proteins, to explore the effect of AXIN1/2 stabilisation on Wnt signalling. It is important to note that tankyrase inhibitors are currently under preclinical investigation in colorectal cancer. They found that tankyrase inhibition failed to increase AXIN1 stability and block Wnt signalling in AXIN2 knockout cells. Moreover, upon investigating the AXIN1/2-tankyrase interaction further, they demonstrated that AXIN2 promotes AXIN1 degradation by first recruiting AXIN1 to tankyrase. Therefore, the loss of AXIN2 leads to a decoupling of the AXIN2/tankyrase-mediated degradation of AXIN1. They conclude that their findings have important implications for tankyrase inhibition-based treatments in colorectal cancer. As AXIN2 is a transcriptional target of β-catenin and a negative feedback regulator of Wnt signalling, tankyrase inhibition would initially lead to stabilisation of the AXIN1/2 destruction complex. However, sustained inhibition of this pathway would be a challenge as this would lead to depletion of AXIN2, thus releasing Wnt signalling from the negative feedback loop operated by AXIN2. The authors further speculate that the temporal pattern of administering tankyrase inhibitors might be a possible solution to this, and that an ‘oscillating’ treatment strategy might allow the recovery of AXIN2 expression. This study highlights the complex and often surprising nature of seemingly simple signalling pathways and emphasises the challenges for drug discovery and development. It also suggests that the timing and frequency of treatments administered could have important implications for the outgrowth of resistance mechanisms. HK is employed by FEBS and is an Editor at The FEBS Journal.