LIN, Z. | bioRxiv Science

bioRxiv2021

Structural and functional elucidation of NF-κB signaling by the p75 neurotrophin receptor through recruitment of TRADD

p75 neurotrophin receptor (p75NTR) is a critical mediator of neuronal death and tissue remodeling and has been implicated in various neurodegenerative diseases. The death domain (DD) of p75NTR is an intracellular signaling hub and has been shown to interact with diverse adaptor proteins. However, the structural mechanism and physiological relevance of the adaptor protein TRADD in neuronal p75NTR signaling remain poorly understood. Here we report an NMR structure of the complex between p75NTR-DD and TRADD-DD and elucidate the structural basis of specific DD recognition in the p75NTR/TRADD signaling pathway. Furthermore, we identify spatiotemporal overlap of p75NTR and TRADD expression in developing cerebellar granule neurons (CGNs) at early postnatal stages and reveal the functional role of TRADD recruitment to p75NTR in the regulation of canonical NF-{kappa}B signaling and cell survival in CGNs. Our results provide a new structural framework for understanding how the recruitment of TRADD to p75NTR through DD interactions creates a membrane-proximal platform to propagate downstream signaling in developing neurons.

biophysics↗

bioRxiv2020

Salmonella Enteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein

Autophagy is a cellular process to clear pathogens. Salmonella enterica serovar Enteritidis (S.E) has emerged as one of the most important food-borne pathogens. However, major studies still focus on Salmonella enterica serovar Typhimurium. Here, we reported that AvrA, a S. Enteritidis effector, inhibited autophagy to promote bacterial survival in the host. We found that AvrA regulates the conversion of LC3 I into LC3 II and the enrichment of lysosomes. Beclin-1, a key molecular regulator of autophagy, was decreased after AvrA expressed strain colonization. In S.E-AvrA--infected cells, we found the increases of protein levels of p-JNK and p-c-Jun and the transcription level of AP-1. AvrA-reduction of Beclin-1 protein expression is through the JNK pathway. The JNK inhibitor abolished the AvrA-reduced Beclin-1 protein expression. Moreover, we identified that the AvrA mutation C186A abolished its regulation of Beclin-1 expression. In addition, AvrA protein interacted with Beclin-1. In organoids and infected mice, we explored the physiologically related effects and mechanism of AvrA in reducing Beclin-1 through the JNK pathway, thus attenuating autophagic responses. ImportanceSalmonella Enteritidis is an important pathogen with a public health concern and farm production risk, yet the host-pathogen interactions that govern the survival of S. Enteritidis infections are incompletely understood. Anti-bacterial autophagy provides potent cell-autonomous immunity against bacterial colonization. Here, we report that a new role for effector AvrA of S. Enteritidis in the reduction of Beclin-1 protein expression through the JNK pathway and the attenuation of the autophagic response in intestinal epithelial cells. This finding not only indicates an important role of S. Enteritidis effector in reducing host protein as a strategy to suppress autophagy, but also suggests manipulating autophagy as a new strategy to treat infectious diseases.

microbiology↗