Opposing roles of E3 ligases TRIM23 and TRIM21 in regulation of ion channel ANO1 protein levels.

Anoctamin-1 (ANO1) (TMEM16A) is a calcium-activated chloride channel that plays critical roles in diverse physiological processes, such as sensory transduction and epithelial secretion. ANO1 levels have been shown to be altered under physiological and pathological conditions, although the molecular mechanisms that control ANO1 protein levels remain unclear. The ubiquitin-proteasome system is known to regulate the levels of numerous ion channels, but little information is available regarding whether and how ubiquitination regulates levels of ANO1. Here, we showed that two E3 ligases, TRIM23 and TRIM21, physically interact with the C terminus of ANO1. In vitro and in vivo assays demonstrated that whereas TRIM23 ubiquitinated ANO1 leading to its stabilization, TRIM21 ubiquitinated ANO1 and induced its degradation. Notably, ANO1 regulation by TRIM23 and TRIM21 is involved in chemical-induced pain sensation, salivary secretion, and heart-rate control in mice, and TRIM23 also mediates ANO1 upregulation induced by epidermal growth factor treatment. Our results suggest that these two antagonistic E3 ligases act together to control ANO1 expression and function. Our findings reveal a previously unrecognized mechanism for regulating ANO1 protein levels and identify a potential molecular link between ANO1 regulation, epidermal growth factor, and other signaling pathways.

Inflammatory cytokine signalling in vulvovaginal candidiasis: a hot mess driving immunopathology.

Protective immunity to opportunistic fungal infections consists of tightly regulated innate and adaptive immune responses that clear the infection. Immune responses to infections of the vaginal mucosa by Candida species are, however, an exception. In the case of vulvovaginal candidiasis (VVC), the inflammatory response is associated with symptomatic disease, rather than that it results in pathogen clearance. As such VVC can be considered an inflammatory disease, which is a significant public health problem due to its predominance as a female-specific fungal infection. Particularly, women with recurrent VVC (RVVC) suffer from a significant negative impact on their quality of life and mental health. Knowledge of the inflammatory pathogenesis of (R)VVC may guide more effective diagnostic and therapeutic options to improve the quality of life of women with (R)VVC. Here, we review the immunopathogenesis of (R)VVC describing several elements that induce an inflammatory arson, starting with the activation threshold established by vaginal epithelial cells that prevent unnecessary ignition of inflammatory responses, epithelial and inflammasome-dependent immune responses. These inflammatory responses will drive neutrophil recruitment and dysfunctional neutrophil-mediated inflammation. We also review the, sometimes controversial, findings on the involvement of adaptive and systemic responses. Finally, we provide future perspectives on the potential of some unexplored cytokine axes and discuss whether VVC needs to be subdivided into subgroups to improve diagnosis and treatment.