Signaling Functions of Intramembrane Aspartyl-Proteases

Intriguing parasites and intramembrane proteases.

Rhomboid intramembrane proteases occur throughout the kingdoms of life. In this issue of Genes & Development, Baxt and colleagues (pp. 1636-1646) report that the single proteolytic rhomboid (EhROM1) from Entamoeba histolytica cleaves cell surface galactose-binding or N-acetylgalactosamine-binding (Gal/Gal-NAc) lectins. EhROM1 and lectins colocalize during phagocytosis and receptor capping. EhRO...

Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer’s disease

The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/PS2) underlie production of β-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the γ-cleavage activities of PSENs that produce Aβ, but not the ε-like cleavage activity that release physiologically essential transcription activators,...

Regulated intramembrane proteolysis: signaling pathways and biological functions.

Intramembrane cleavage of transmembrane proteins is a fundamental cellular process. Several enzymes capable of releasing domains of integral membrane proteins have been described. Transmembrane protein proteolytic cleavage is regulated and involved not only in degrading membrane spanning segments but also in generating messengers that elicit biological responses. This review examines the role o...

The intramembrane proteases signal Peptide peptidase-like 2a and 2b have distinct functions in vivo.

We reported recently that the presenilin homologue signal peptide peptidase-like 2a (SPPL2a) is essential for B cell development by cleaving the N-terminal fragment (NTF) of the invariant chain (li, CD74). Based on this, we suggested that pharmacological modulation of SPPL2a may represent a novel approach to deplete B cells in autoimmune disorders. With regard to reported overlapping substrate ...

Sheddases and intramembrane-cleaving proteases: RIPpers of the membrane. Symposium on regulated intramembrane proteolysis.