The
Lactobacillaceae
are an intensively studied family of bacteria widely used in fermented food and probiotics, and many are native to the gut and vaginal microbiota of humans and other animals. Various studies have shown that specific
Lactobacillaceae
species produce metabolites that can inhibit the colonization of fungal and bacterial pathogens, but less is known about how
Lactobacillaceae
affect individual bacterial species in the endogenous animal microbiota. Here, we show that numerous
Lactobacillaceae
species inhibit the growth of the
Lachnospiraceae
family and the S24-7 group, two dominant clades of bacteria within the gut. We demonstrate that inhibitory activity is a property common to homofermentative
Lactobacillaceae
species, but not to species that use heterofermentative metabolism. We observe that homofermentative
Lactobacillaceae
species robustly acidify their environment, and that acidification alone is sufficient to inhibit growth of
Lachnospiraceae
and S24-7 growth, but not related species from the
Clostridiales
or
Bacteroidales
orders. This study represents one of the first in-depth explorations of the dynamic between
Lactobacillaceae
species and commensal intestinal bacteria, and contributes valuable insight toward deconvoluting their interactions within the gut microbial ecosystem.
The deubiquitinating enzyme, USP7, regulates the turnover of proteins involved in many diverse cellular processes, including maintenance of genome stability, tumour suppression, epigenetics, DNA replication, cell division, and immune response. Previously defined USP7 substrates, including GMPS, UHRF1, and ICP0, were characterized to interact with the C-terminal domain of USP7 via a KxxxK motif. We identified a common motif in Enhancer of Zeste 2 (EZH2), a histone methyltransferase and the catalytic component of the Polycomb Repressive Complex 2 (PRC2). PRC2 is responsible for methylating Histone 3 Lys27 (H3K27) leading to transcriptional repression of genes involved in differentiation and development. The interaction between USP7 and EZH2 was demonstrated by GST pull-down and co-immunoprecipitation experiments. We co-crystallized Ubl123 of USP7 with an EZH2 peptide containing the predicted interaction site and characterized the structural basis of the interaction, identifying the key residues involved. Mutagenesis studies of these residues demonstrated abolished binding between USP7 and EZH2. The functional relationship between USP7 and EZH2 was investigated using USP7 knock-down and knock-out experiments which corresponded with reduced EZH2 levels in HCT116 carcinoma cells and decreased H3K27Me3 levels in HCT116 USP7 knockout cells respectively. These findings reveal that USP7 regulates both the stability and function of EZH2.
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