FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation

Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.     

Urbanization impacts on the trophic guild composition of bird communities

Urbanization transforms the landscape and generates loss of pristine habitats. We investigated the urbanization effect on bird communities in a growing South American city (Santa Fe, Argentina) and hypothesized that if habitat structure and human disturbance change along an urban gradient, the richness and abundance of trophic guilds should also vary accordingly. We placed 50 transects 100 m long × 50 m wide in five districts with different levels of urbanization, determined by habitat structure variables. We recorded the number and abundance of species and the amount of pedestrians and vehicles passing through each transect. We recorded 23% of all bird species known for the Santa Fe province and categorized them within 19 trophic guilds. The percentage of area covered by herbaceous vegetation, water bodies and trees and shrubs had a positive relationship with the richness and abundance of most of trophic guilds (hawking aerial, terrestrial, bark and foliage insectivores; terrestrial and generalized granivores; generalized, aquatic diving and foliage omnivores; hawking aerial, aquatic diving and striding carnivores; nectarivores; and aquatic filters). Pavement surface and human disturbance variables had a negative relationship with the richness, and high buildings and pavement surface had a positive relationship with the abundance of terrestrial omnivores and coursing aerial insectivores. Variation partitioning revealed that habitat structure and human disturbance were better predictors of the richness than the abundance of each trophic guild. Results showed that trophic guilds associated to vegetation strata were seen to increase their richness and abundance towards green areas, even if they presented generalist or specialist habits. Urban planners should conserve or manage the surrounded natural spaces when the growth of the city is directed to these areas and increase the availability of environmental features within the urban matrix.     

CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN

The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN. Importantly, SMN acetylation enhances its cytoplasmic localization, causes depletion of CBs, and reduces the accumulation of snRNPs in nuclear speckles. In contrast, the acetylation-deficient SMNK119R mutant promotes formation of CBs and a novel category of promyelocytic leukemia (PML) bodies enriched in this protein. Acetylation increases the half-life of SMN protein, reduces its cytoplasmic diffusion rate and modifies its interactome. Hence, SMN acetylation leads to its dysfunction, which explains the ineffectiveness of HDAC (histone deacetylases) inhibitors in SMA therapy despite their potential to increase SMN levels.