The primary cilium constitutes an organelle that orchestrates signal transduction independently from the cell body. Dysregulation of this intricate molecular architecture leads to severe human diseases, commonly referred to as ciliopathies. However, the molecular underpinnings how ciliary signaling orchestrates a specific cellular output remain elusive. By combining spatially resolved optogenetics with RNA sequencing and imaging, we reveal a novel cAMP signalosome that is functionally distinct from the cytoplasm. We identify the genes and pathways targeted by the ciliary cAMP signalosome and shed light on the underlying mechanisms and downstream signaling. We reveal that chronic stimulation of the ciliary cAMP signalosome transforms kidney epithelia from tubules into cysts. Counteracting this chronic cAMP elevation in the cilium by small molecules targeting activation of phosphodiesterase‐4 long isoforms inhibits cyst growth. Thereby, we identify a novel concept of how the primary cilium controls cellular functions and maintains tissue integrity in a specific and spatially distinct manner and reveal novel molecular components that might be involved in the development of one of the most common genetic diseases, polycystic kidney disease.

The primary cilium is a solitary, microtubule-based membrane protrusion extending from the surface of quiescent cells that senses the cellular environment and triggers specific cellular responses. The functions of primary cilia require not only numerous different components but also their regulated interplay. The cilium performs highly dynamic processes, such as cell cycle-dependent assembly and disassembly as well as delivery, modification, and removal of signaling components to perceive and process external signals. On a molecular level, these processes often rely on a stringent control of key modulatory proteins, of which the activity, localization, and stability are regulated by post-translational modifications (PTMs). While an increasing number of PTMs on ciliary components are being revealed, our knowledge on the identity of the modifying enzymes and their modulation is still limited. Here, we highlight recent findings on cilia-specific phosphorylation and ubiquitylation events. Shedding new light onto the molecular mechanisms that regulate the sensitive equilibrium required to maintain and remodel primary cilia functions, we discuss their implications for cilia biogenesis, protein trafficking, and cilia signaling processes.

Monilinia fructicola is a destructive pathogen causing brown rot on stone fruits worldwide. Though it is best known as a fruit rot pathogen, M. fructicola also causes blossom blight and, subsequently, twig cankers in the spring. Orchard management strategies often overlook cankers as an inoculum source, though they are an inoculum source of both blossom and fruit infections. In this study, we analyzed the role of cankers as storage structures for diverse genotypes of M. fructicola, examining whether multiple genotypes can be transmitted from blossom to canker. Fungal spores from blossoms, and 2 months later from their corresponding cankers, were collected from a conventional and an unsprayed orchard in 2015 and 2016. Simple sequence repeat markers were used to genotype 10 to 20 single spores from each of four blossom/canker pairs per orchard. Individual blossoms and cankers were detected containing up to four and five genotypes, respectively. The average number of genotypes in blossoms and corresponding cankers were not significantly different (P = 0.690) across both years and farms, showing that a bottleneck for genetic diversity was not generated during the transition from blossom to canker. The average number of genotypes unique to blossom or canker was not significantly different (P = 0.569) and no significant effect of farm (P = 0.961) or year (P = 0.520) was observed, although blossoms had a numerically greater number of unique genotypes in both cases. In conclusion, a single blossom may be infected by one or more genotypes of M. fructicola, and this diversity is being preserved in the corresponding canker. This information implicates M. fructicola cankers as diversity storehouses, and may also apply to other Monilinia spp. and fungal diseases that initiate in reproductive tissue.