The Structure and Biological Function of CREG

Abstract

The cellular repressor of E1A-stimulated genes (CREG) is a 220 amino acid glycoprotein structurally similar to oxidoreductases. However, CREG does not have enzymatic activities because it cannot bind to the cofactor flavin mononucleotide. Although CREG can be secreted, it is mainly an intracellular protein localized in the endocytic-lysosomal compartment. It undergoes proteolytic maturation mediated by lysosomal cysteine proteases. Biochemical studies have demonstrated that CREG interacts with mannose-6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R) and exocyst Sec8. CREG inhibits proliferation and induces differentiation and senescence when overexpressed in cultured cells. In Drosophila, RNAi-mediated knockdown of CREG causes developmental lethality at the pupal stage. In mice, global deletion of the CREG1 gene leads to early embryonic death. These findings establish an essential role for CREG in development. CREG1 haploinsufficient and liver-specific knockout mice are susceptible to high fat diet-induced obesity, hepatic steatosis and insulin resistance. The purpose of this review is to provide an overview of what we know about the biochemistry and biology of CREG and to discuss the important questions that remain to be addressed in the future.

Keywords: CREG; differentiation; exocyst; lysosome; mannose-6-phosphate/insulin-like growth factor-2 receptor; metabolism; proliferation.

FIGURE 1

The biological activity of CREG and possible mechanisms of action. CREG binds to mannose-6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R) and may enhance autophagy through M6P/IGF2R-mediated delivery of lysosomal hydrolases from Golgi to the lysosome. CREG may also facilitate M6P/IGF2R-mediated internalization and degradation of extracellular IGF-2, thereby inhibiting cell growth and promoting differentiation. CREG interacts with the exocyst component Sec8 and promotes cellular differentiation and cell-cell junction formation. In addition, CREG acts synergistically with p16^INK4a to induce cellular senescence.