Melanin production in the skin protects us against UV damage, but how? These authors show that upon UV exposure MC1R enters primary cilia and interacts with the BBSome, triggering the downstream signalling that stimulates melanogenesis. Red-haired people have a genetic variation in MC1R that affects this interaction, leading to defective melanin production.
The hedgehog signal transduction pathway has an important role in development; it proceeds through the atypical GPCR protein SMOOTHENED (SMO), which regulates the transcription factor GLI by direct binding to PKA-C. This study shows that the GPCR kinase 2 activates SMO in primary cilia, allowing its binding to PKA-C and pathway activation in various cellular and in vivo models.
Most research on retinal degeneration has focused on the ciliated photoreceptor cells, but the role of primary cilia in other ocular cell types has largely been ignored. This study shows that the primary cilium in the retinal pigment epithelium is essential for development and for the proper functioning of this tissue; its absence results in retinal degeneration.
Cilia are sensory organelles that project from the surface of almost all cells. Nephronophthisis (NPH) and NPH-related ciliopathies are degenerative genetic diseases caused by mutation of cilia-associated genes. These kidney disorders are characterized by progressive loss of functional tubular epithelial cells which is associated with inflammation, progressive fibrosis, and cyst formation, ultimately leading to end-stage renal disease. However, disease mechanisms remain poorly understood. Here, we show that targeted deletion of cilia in renal epithelial cells enhanced susceptibility to necroptotic cell death under inflammatory conditions. Treatment of non-ciliated cells with tumor necrosis factor (TNF) α and the SMAC mimetic birinapant resulted in Ripk1-dependent cell death, while viability of ciliated cells was almost not affected. Cell death could be enhanced and shifted toward necroptosis by the caspase inhibitor emricasan, which could be blocked by inhibitors of Ripk1 and Ripk3. Moreover, combined treatment of ciliated and non-ciliated cells with TNFα and cycloheximide induced a cell death response that could be partially rescued with emricasan in ciliated cells. In contrast, non-ciliated cells responded with pronounced cell death that was blocked by necroptosis inhibitors. Consistently, combined treatment with interferon-γ and emricasan induced cell death only in non-ciliated cells. Mechanistically, enhanced necroptosis induced by loss of cilia could be explained by induction of Ripk3 and increased abundance of autophagy components, including p62 and LC3 associated with the Ripk1/Ripk3 necrosome. Genetic ablation of cilia in renal tubular epithelial cells in mice resulted in TUNEL positivity and increased expression of Ripk3 in kidney tissue. Moreover, loss of Nphp1, the most frequent cause of NPH, further increased susceptibility to necroptosis in non-ciliated epithelial cells, suggesting that necroptosis might contribute to the pathogenesis of the disease. Together, these data provide a link between cilia-related signaling and cell death responses and shed new light on the disease pathogenesis of NPH-related ciliopathies.
#Introduction to #ScienceMastodon
I am a #Cilia #Islet #Biologist and endocrinologist at WashU in St Louis.
#PrimaryCilia because it is the center of the cell and my world.
Unafraid to challenge convention and do difficult experiments (because we don’t know better).
Also #Microscopy because seeing is believing.
#Cilia #cell #center #cytoskeleton #betacell #signaling #diabetes
Image credit #WUCCI and Alex Polino
PLOS Biology
SFB1403
Jing Hughes