Biology subjects

Ni, K.

Publications and source records attributed to Ni, K..

3 recordsLinked to original sources

bioRxiv2021

Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo

The eIF2 initiation complex is central to maintaining a functional translation machinery. Extreme stress such as life-threatening sepsis exposes vulnerabilities in this tightly regulated system, resulting in an imbalance between the opposing actions of kinases and phosphatases on the main regulatory subunit eIF2. Here, we report that translation shutdown is a hallmark of established sepsis-induced kidney injury brought about by excessive eIF2 phosphorylation and sustained by blunted expression of the counterregulatory phosphatase subunit Ppp1r15a. We determined that the blunted Ppp1r15a expression persists because of the presence of an upstream open reading frame (uORF). Overcoming this barrier with genetic approaches enabled the derepression of Ppp1r15a, salvaged translation and improved kidney function in an endotoxemia model. We also found that the loss of this uORF has broad effects on the composition and phosphorylation status of the immunopeptidome that extended beyond the eIF2 axis. Collectively, our findings define the breath and potency of the highly conserved Ppp1r15a uORF and provide a paradigm for the design of uORF-based translation rheostat strategies. The ability to accurately control the dynamics of translation during sepsis will open new paths for the development of therapies at codon level precision.

physiology↗

bioRxiv2021

Transiently increased intercommunity regulation characterizes concerted cell phenotypic transition

Phenotype transition takes place in many biological processes such as differentiation and reprogramming. A fundamental question is how cells coordinate switching of expressions of clusters of genes. Through analyzing single cell RNA sequencing data in the framework of transition path theory, we studied how such a genome-wide expression program switching proceeds in five different cell transition processes. For each process we reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulation network (GRN) along the reaction coordinate. In all processes we observed common pattern that the overall effective number and strength of regulation between different communities increase first and then decrease. The change accompanies with similar change of the GRN frustration, defined as overall conflict between the regulation received by genes and their expression states, and GRN heterogeneity. While studies suggest that biological networks are modularized to contain perturbation effects locally, our analyses reveal a general principle that during a cell phenotypic transition, intercommunity interactions increase to concertedly coordinate global gene expression reprogramming, and canalize to specific cell phenotype as Waddington visioned.

systems biology↗

bioRxiv2021

Assembly status transition offers an avenue for activity modulation of a supramolecular enzyme

Nature has evolved many supramolecular proteins assembled in certain, sometimes even seemingly oversophisticated, morphological manners. The rationale behind such evolutionary efforts is often poorly understood. Here we provide atomic-resolution insights into how the dynamic building of a structurally complex enzyme with higher-order symmetry offers amenability to intricate allosteric regulation. We have established the functional coupling between enzymatic activity and protein morphological states of glutamine synthetase (GS), an old multi-subunit enzyme essential for cellular nitrogen metabolism. Cryo-EM structure determination of GS in both the catalytically active and inactive assembly states allows us to reveal an unanticipated self-assembly-induced dynamics-driven allosteric paradigm, in which the remote interactions between two subcomplex entities significantly rigidify the otherwise structurally fluctuating active sites, thereby regulating activity. We further show in vivo evidences that how the enzyme morphology transitions could be modulated by cellular factors on demand. Collectively, our data present an example of how assembly status transition offers an avenue for allosteric modulation, and sharpens our mechanistic understanding of allostery, dynamics, cooperativity, and other complex functional and regulatory properties of supramolecular enzymes.

biochemistry↗