Chemical Biology
C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neuronsExtracellularly delivered poly-GAs are internalised into astrocytes via an endocytosis-dependent pathway and then spread to motor neurons, implying non-cell autonomous mechanisms in C9ORF72-ALS/FTD.
Adipose tissue–specific ablation of Ces1d causes metabolic dysregulation in miceCes1d is a crucial enzyme in adipose tissue. Here, we found a high level of Ces1d translocates onto lipid droplets where it digests the lipids to produce unique fatty acids which are key for glucose and lipid metabolism.
Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivityThe tumor suppressor protein p53 inhibits ferroptosis by reducing the consumption of glutathione in nucleotide biosynthesis.
USP30 sets a trigger threshold for PINK1–PARKIN amplification of mitochondrial ubiquitylationA new inhibitor of the deubiquitylase USP30, an actionable target relevant to Parkinson’s Disease, is introduced and characterised for parameters related to mitophagy.
Caspase-1 interdomain linker cleavage is required for pyroptosisThe related human NLRP1 and CARD8 form ASC-dependent and ASC-independent inflammasomes, respectively, both of which require pro-caspase-1 interdomain linker processing for the induction of pyroptosis.
Phenotypic proteomic profiling identifies a landscape of targets for circadian clock–modulating compoundsThis study provides comprehensive insights into the mechanism of action and cellular effects of circadian period–modulating compounds, which is critical for clearly defining molecular targets to modulate daily rhythms for therapeutic benefit.
Plasmalogen loss caused by remodeling deficiency in mitochondria31P NMR unveils cell type–dependent losses of plasmalogen in the chain remodeling–deficient brain, liver, kidney, and lymphoblast in association with aberrant mitochondrial function and morphology.
Ncl1-mediated metabolic rewiring critical during metabolic stressAccumulation of cysteine induces translational defects and metabolic rewiring that are abrogated by leucine in a transfer RNA (tRNA) methyltransferase NCL1-dependent manner in yeast.
Human DNA polymerase delta is a pentameric holoenzyme with a dimeric p12 subunitThe subunit p12 of human DNA polymerase delta (hPolδ) can dimerize, facilitating its interaction with PCNA and suggesting that hPolδ exists in a pentameric form in the cell.
Chemical genetic identification of GAK substrates reveals its role in regulating Na+/K+-ATPaseNovel GAK phosphorylation targets are identified using chemical genetic methods. One of the substrates is the α subunit of the Na+/K+-ATPase, phosphorylation of which is necessary for its surface trafficking from endosomes. Conserved functions of NAK family kinases are described.