Significance Newly synthesized proteins undergo a strict quality-control checkpoint, and misfolded secretory proteins are targeted across the endoplasmic reticulum membrane back to the cytosol for proteasome degradation. This process requires tagging errant proteins with ubiquitin by an E3 ubiquitin ligase. In a genetic screen we identified TMEM129 as a novel and unusual E3 ligase. TMEM129 is hijacked by the human cytomegalovirus to degrade MHC-I signaling molecules and avert immune recognition of the infected cell. We suggest TMEM129 is an important ligase in the turnover of misfolded secretory proteins within a novel endoplasmic reticulum-associated degradation complex.
Endoplasmic-reticulum-associated protein degradation
Mitochondrial quality control is essential to maintain cellular homeostasis and is achieved by removing damaged, ubiquitinated mitochondria via Parkin-mediated mitophagy. Here, we demonstrate that MYO6 (myosin VI), a unique myosin that moves toward the minus end of actin filaments, forms a complex with Parkin and is selectively recruited to damaged mitochondria via its ubiquitin-binding domain. This myosin motor initiates the assembly of F-actin cages to encapsulate damaged mitochondria by forming a physical barrier that prevents refusion with neighboring populations. Loss of MYO6 results in an accumulation of mitophagosomes and an increase in mitochondrial mass. In addition, we observe downstream mitochondrial dysfunction manifesting as reduced respiratory capacity and decreased ability to rely on oxidative phosphorylation for energy production. Our work uncovers a crucial step in mitochondrial quality control: the formation of MYO6-dependent actin cages that ensure isolation of damaged mitochondria from the network.
T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8
From "Quantitative proteomic analysis of SARS-CoV-2 infection of primary human airway ciliated cells and lung epithelial cells demonstrates the effectiveness of SARS-CoV-2 innate immune evasion"
Single time-point (48 h) SARS-CoV-2 proteomics experiment
Database : Protein database Accession : Uniprot Accession Entry : Uniprot Entry Taxonomy : Taxonomy ID Gene.ID : Gene ID Description : Gene Description #Unique : # Unique peptides detected Subsequent columns : Normalised TMT reporter ion intenisty for each replicate In addition to conditions displayed in the explanatory figure, this dataset Includes proteomic analysis of two ACE2 high Calu-3 clones, Clone 28 and Clone 37.
Hypoxia Inducible transcription Factors (HIFs) are principally regulated by the 2-oxoglutarate and Iron(II) prolyl hydroxylase (PHD) enzymes, which hydroxylate the HIFα subunit, facilitating its proteasome-mediated degradation. Observations that HIFα hydroxylation can be impaired even when oxygen is sufficient emphasise the importance of understanding the complex nature of PHD regulation. Here, we use an unbiased genome-wide genetic screen in near-haploid human cells to uncover cellular processes that regulate HIF1α. We identify that genetic disruption of the Vacuolar H+ ATPase (V-ATPase), the key proton pump for endo-lysosomal acidification, and two previously uncharacterised V-ATPase assembly factors, TMEM199 and CCDC115, stabilise HIF1α in aerobic conditions. Rather than preventing the lysosomal degradation of HIF1α, disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation. Iron supplementation directly restores PHD catalytic activity following V-ATPase inhibition, revealing important links between the V-ATPase, iron metabolism and HIFs.
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