Horizontal gene transfer-initiated reorganization of lipid metabolism drives lifestyle innovation in a eukaryote

Horizontal gene transfer is a source of metabolic innovation and adaptation to new environments. Yet, how horizontally transferred metabolic functionalities are integrated into host cell biology remains an open question. Here, we use the fission yeast Schizosaccharomyces japonicus to probe how eukaryotic lipid metabolism is rewired in response to the acquisition of a horizontally transferred squalene-hopene cyclase Shc1. We show that Shc1-dependent production of hopanoids, the structural mimics of eukaryotic sterols, allows S. japonicus to thrive in anoxia, where sterol biosynthesis is not possible. We further demonstrate that glycerophospholipid fatty acyl asymmetry, prevalent in S. japonicus, is crucial for accommodating both sterols and hopanoids in membranes, and explain how Shc1 functions alongside the native sterol biosynthetic pathway to support membrane properties. Through engineering experiments in the sister species S. pombe, which naturally lacks Shc1, we show that the acquisition of Shc1 may entail new physiological traits; however, to maximize Shc1 performance, sterol biosynthesis must be dampened. Our work sheds new light on the mechanisms underlying cellular integration of horizontally transferred genes in eukaryotes and provides broader insights into the evolution of membrane organization and function.