Moonlighting and pleiotropy within two regulators of the degradation machinery: the proteasome lid and the CSN.

The distinction between pleiotrotic and moonlighting roles of proteins is challenging; however, this distinction may be clearer when it comes to multiprotein complexes. Two examples are the proteasome lid and the COP9 signalosome (CSN), which are twin enzymes with 1:1 paralogy between subunits. In each complex, one out of eight subunits harbours a JAMM/MPN⁺ metalloprotease motif. This motif contributes the canonical activity of each complex: hydrolysis of covalently attached ubiquitin by Rpn11 in the proteasome lid and hydrolysis of ubiquitin-related 1 (Rub1/Nedd8) from Cullins by Csn5 in the CSN. In both complexes, executing this activity suggests pleiotropic effects and requires an assembled full complex. However, beyond canonical functions, both Rpn11 and Csn5 are involved in additional unique, complex-independent functions, herein referred to as moonlighting activities.