The indispensable role of autophagy in lens morphogenesis

FYVE and coiled-coil domain containing 1 (FYCO1) is expressed ubiquitously and is required for microtubule-dependent, plus-end-directed transport of autophagic vesicles. We previously reported the loss of function mutations in FYCO1 responsible for cataractogenesis with no other ocular and/or extra-ocular phenotype. Here, we show that Fyco1-/- lenses recapitulated the cataract phenotype and exhibited diminished autophagy, consistent with a critical role of Fyco1 and autophagy in lens morphogenesis. Transcriptome coupled with proteome and metabolome profiling identified many differentially expressed, autophagy-related, genes, proteins, and lipids, respectively in Fyco1-/- lenses. Flow cytometry of FYCO1 (c.2206C>T) knock-in (KI) human lens epithelial (HLE) cell line confirmed reduced amounts of membrane-bound LC3B-II and autophagic vesicles resulting from the loss of FYCO1. Transmission electron microscopy showed persistent organelle mass in Fyco1-/- lenses and FYCO1 KI lens-like organoid structures, which were further confirmed through western blot analysis. In summary, our data show that the absence of FYCO1 causes diminished autophagy, delayed organelle degradation, and cataractogenesis. These data support the model of FYCO1 supplementing basal autophagy in the lens to meet the physiological necessity of high autophagy levels required during lens fiber cell differentiation and lack thereof results in delayed organelle removal.