Decoding BIG: how one protein influences multiple pathways

A major strength of forward genetic screens is their unbiased nature: the plant reveals which genes underlie a physiological process. Yet this strength often presents a new challenge: determining the biochemical basis of the mutant phenotype. BIG/DARK OVEREXPRESSION OF CAB1/TRANSPORT INHIBITOR RESPONSE3 encodes an exceptionally large (∼0.5 MDa) protein identified in diverse genetic screens. big mutants have smaller stature, reduced elongation growth and apical dominance, and defects in lateral root formation, phenotypes consistent with disrupted auxin gradients. However, they also display altered stomatal behaviour, circadian regulation, pathogen responses, and changes in other hormone pathways. This broad pleiotropy points to wide-ranging roles in signalling and development, yet the biochemical function of BIG remained unresolved for more than three decades. Recently, we showed that BIG participates in the Arg/N-degron pathways, a specialised form of proteostasis in which the half-lives of proteins are influenced by their N-terminal (Nt) residues. However, this does not explain the pleiotropic phenotypes of big mutants. New structural and functional clues from the mammalian homologue ubiquitin amino-end recognising protein 4 (UBR4) point to wider proteostatic roles for BIG, providing a potential explanation for the impacts of BIG on plant physiology and a rich source of hypotheses for future studies.