Autophagosomes coordinate an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling.

Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα/β) and regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis, partly via its AKAP11 scaffold. Mutations in AKAP11 drive schizophrenia and bipolar disorders (SZ-BP) through unknown mechanisms.

Functional genetics reveals modulators of anti-microtubule drug sensitivity.

Microtubules play essential roles in diverse cellular processes and are important pharmacological targets for treating human disease. Here, we sought to identify cellular factors that modulate the sensitivity of cells to anti-microtubule drugs. We conducted a genome-wide CRISPR/Cas9-based functional genetics screen in human cells treated with the microtubule-destabilizing drug nocodazole or the microtubule-stabilizing drug taxol.

The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.

The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders.

PITTching in for lysosome repair.

Lysosomes, guardians of cell health, can sustain physical damage from biological, mechanical, and chemical stressors, necessitating dedicated mechanisms for their upkeep. In a recent issue of Nature, Tan and Finkel report the discovery of a lysosomal repair pathway controlled by phosphoinositides, which operates via bulk transport of lipids across ER-lysosome contacts.

Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1.

Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified lysosomal cholesterol signaling (LYCHOS, previously annotated as G protein-coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic target of rapamycin complex 1 (mTORC1). Cholesterol bound to the amino-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation.

Mitochondrial Fission and Fusion Dynamics Generate Efficient, Robust, and Evenly Distributed Network Topologies in Budding Yeast Cells.

The simplest configuration of mitochondria in a cell is as small separate organellar units. Instead, mitochondria often form a dynamic, intricately connected network. A basic understanding of the topological properties of mitochondrial networks, and their influence on cell function is lacking.