The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress

The ribosome has emerged as a signalling hub that can sense metabolic perturbations and coordinate responses that either restore homeostasis or initiate cell death. The range of insults that signal via the ribosome and the mechanisms governing such cell fate decisions remain uncharacterized. Here we identify the atypical E3 ligase HOIL-1 as an unexpected node in the ribosome signalling network that resolves cellular stress. We find that truncating HOIL-1 mutations associated with dilated cardiomyopathy exacerbate cardiac dysfunction in mice and broadly sensitize cells to nutrient and translational stress. These diverse signals converge on the MAP3K ZAKα, a sentinel of ribotoxic stress. Mechanistically, HOIL-1 promotes ribosome ubiquitination and facilitates cytoprotective ribosome-associated quality control. HOIL-1 loss of function causes glucose starvation to become ribotoxic, leading to ZAKα-dependent ATF4 activation and disulfidptosis driven by the cystine–glutamate antiporter xCT. These data reveal a molecular circuit controlling cell fate during nutrient stress and establish the ribosome as a signalosome that responds to cellular glucose levels. Douglas et al. study the E3 ligase HOIL-1, mutated in patients with a type of myopathy. Mutant HOIL-1 influences the sensitivity to disulfidptosis initiated by ZAKα–ATF4 in glucose starvation and interferes with the cytoprotective roles of PABPC1 and MKRN1.