Publication in detail

Life Sci Alliance. 2019 Jan 28;2(1). pii: e201800273. doi: 10.26508/lsa.201800273. Print 2019 Feb.

Redundant and nonredundant organismal functions of EPS15 and EPS15L1.

Milesi, C; Alberici, P; Pozzi, B; Oldani, A; Beznoussenko, GV; Raimondi, A; Soppo, BE; Amodio, S; Caldieri, G; Malabarba, MG; Bartalot, G; Confalonieri, S; Parazzoli, D; Mironov, AA; Tacchetti, C; Fiore, PP Di; Sigismund, S; Offenhäuser, N

IFOM, Fondazione Istituto FIRC (Fondazione Italiana per la Ricerca sul Cancro) di Oncologia Molecolare, Milan, Italy. Cogentech Società Benefit Srl, Milan, Italy. Experimental Imaging Centre, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy. IEO, Istituto Europeo di Oncologia IRCCS (Istituti di Ricovero e Cura a Carattere Scientifico), Milan, Italy. Università degli Studi di Milano, Dipartimento di Oncologia ed Emato-oncologia, Milan, Italy. Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.

EPS15 and its homologous EPS15L1 are endocytic accessory proteins. Studies in mammalian cell lines suggested that EPS15 and EPS15L1 regulate endocytosis in a redundant manner. However, at the organismal level, it is not known to which extent the functions of the two proteins overlap. Here, by exploiting various constitutive and conditional null mice, we report redundant and nonredundant functions of the two proteins. EPS15L1 displays a unique nonredundant role in the nervous system, whereas both proteins are fundamental during embryo development as shown by the embryonic lethality of -Eps15/Eps15L1-double KO mice. At the cellular level, the major process redundantly regulated by EPS15 and EPS15L1 is the endocytosis of the transferrin receptor, a pathway that sustains the development of red blood cells and controls iron homeostasis. Consequently, hematopoietic-specific conditional Eps15/Eps15L1-double KO mice display traits of microcytic hypochromic anemia, due to a cell-autonomous defect in iron internalization.

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