Microprotein PLUM encoded by Lin28b uORF is a cytoplasmic determinant of pluripotency and embryonic development.

Abstract

The crosstalk between translation and metabolism is fundamental for cellular plasticity. While most studies focus on translation within canonical coding regions, the roles of non-canonical open reading frames (ORFs) in metabolic regulation and early development remain unclear. Here, we show that selective translation of an upstream ORF in the 5' untranslated region (UTR) of Lin28b produces an 85-amino acid microprotein, PLUM (pluripotency-associated Lin28b uORF-encoded microprotein). Depletion of PLUM leads to deterministic and synchronized (near 100%) induction of naïve pluripotency and causes embryo implantation defects in vivo. Mechanistically, PLUM depletion dissolves L1td1 condensates and enhances L1td1 binding to pluripotency mRNAs such as Tfcp2l1 and Zfp42, stabilizing them and promoting coordinated gene activation. Concurrently, PLUM loss disrupts P-bodies enriched with a subset of nuclear-encoded mitochondrial mRNA, potentially preventing their degradation. Together, these alterations trigger an early burst of mitochondrial oxidative phosphorylation and synchronized naïve gene expression, accelerating acquisition of the naïve state. Our study identifies the novel uORF-encoded microprotein PLUM as a pluripotency determinant integrating RNA regulation and metabolic remodeling.