Acylamino acid-releasing enzyme (AARE), a bifunctional protease with a potential role in aging

Acylamino acid-releasing enzyme (AARE) is an evolutionary deeply conserved bifunctional serine protease. In its exopeptidase mode, AARE cleaves N-terminally acetylated or otherwise blocked amino acids from the N-terminus of peptides and probably even intact proteins. In its endopeptidase mode, AARE cleaves oxidised proteins at internal positions. Although AARE function was discovered 50 years ago and enzymes from various organisms have been characterized biochemically, the precise role of this protease in cellular physiology remains elusive. Several other names for AARE do exist in literature, such as acylpeptide hydrolase (APEH/ACPH), acylaminoacyl peptidase (AAP) and oxidised protein hydrolase (OPH). Recently, the first AARE null mutants have been described in the model moss Physcomitrella. Comparisons with T-DNA mutants in Arabidopsis revealed a role of AARE in the timing of the developmental transition from the vegetative to the reproductive state as well as in the determination of life span. Loss of AARE function was accompanied by a striking increase in oxidised proteins, which is a hallmark of aging. In mammals, AARE activity is linked to proteasomal function, and dysregulation of AARE function has been observed in different types of cancer and age-related pathologies. Here, we compile the current knowledge on molecular and biological functions of this protease aiming to derive common roles of AARE in cellular physiology, potentially in aging, but also highlight differences between species isoforms.