In this Review, the authors discuss the physiological and biophysical functions of structurally related TMC, TMEM16 and TMEM63 families, with an aim to elucidate the mechanisms that control ion channel gating and mechanisms for scrambling lipids in the lipid membranes.

XPR1 is the only annotated phosphate exporter protein in humans. Recent studies provide mechanistic clues to its cellular function; three posit non-export mechanisms to regulate phosphate homeostasis, while six present high-resolution cryo-EM data supporting a bona fide phosphate channel mechanism controlled by intracellular phosphate levels.

Aneuploidy is a major cause of embryonic failure and miscarriage. A new study identifies genetic variants of ELL3 associated with miscarriage and discovers a novel role for ELL3 in female meiosis.

Targeted protein degradation is a promising drug discovery approach. A study now describes transferrin receptor targeting chimeras (TransTACS), which lysosomally degrade membrane proteins with potent specificity and efficacy. TransTACs reversibly regulate the tumor-killing activity of CAR-T cells and inhibit drug-resistant EGFR-driven cancers in mice.

Mikulski et al. identify a distinct chromatin structure at clustered GBP innate immune genes that preserves a mitotically heritable memory of prior priming by interferon-γ.

Mai and colleagues present cryo-electron microscopy structures of the SPG11–SPG15 and AP5–SPG11–SPG15 complex, offering insights into mechanisms of autophagic lysosome reformation and retrograde trafficking.

Here the authors show that the disruption of OGT expression in mouse embryonic stem cells unleashes TET activity, causing genome-wide decreases in DNA methylation and increases in 5-hydroxymethylcytosine, leading to the derepression of transposable elements and, in certain cases, the activation of nearby genes.

The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactivate BRISC, promoting interferon receptor ubiquitylation and degradation to dampen immune responses.

Lu et al. report a D compartment in Caenorhabditis elegans germ granules, formed by DEAD-box RNA helicase DDX-19 and nuclear pore proteins. This compartment anchors granules to nuclear pores, ensuring compartmentalization, RNA surveillance and germline immortality.

By using cryo-EM and biochemical assays, Loeff et al. reveal the mechanistic basis for the protective function of the oxidoreductase PYROXD1 that maintains the activity of the tRNA ligase complex under aerobic conditions.

We discuss work at the forefront of structural cell biology featured in this issue.

As 2024 closes, we take this opportunity to reflect on the highlights of our 30th anniversary year and consider what the future holds for the field.