Signal peptide peptidase-like 2B (SPPL2B)

Signal peptide peptidase-like 2B (SPPL2B) is an intramembrane-cleaving aspartyl protease localized primarily at endosomes, lysosomes, and the plasma membrane[5]. It belongs to the SPPL family, sharing conserved active site motifs ("YD" and "GxGD") with other family members such as SPPL2A and SPPL3[5][6]. The enzyme catalyzes the proteolytic cleavage of type II transmembrane proteins within their transmembrane domain—a notable physiological substrate is TNF-alpha (in activated dendritic cells), implicating SPPL2B in both innate and adaptive immune responses[5][6][7][3]. Unlike its close homolog SPPL2A (critical for B cell development), SPPL2B is highly expressed in some tissues including the brain and possesses distinct subcellular localization and substrate specificity[1][6]. SPPL2B also influences amyloid precursor protein (APP) processing, potentially linking it to neurodegenerative pathways[5]. There is significant experimental interest in pharmacologically modulating SPPL2B and the broader SPP/SPPL family as a strategy to influence immune responses or proteolytic processing pathways, though selective inhibitors are not yet in clinical use for this target[8][7].

Other names

SPPL2bSignal peptide peptidase like 2BSignal-peptide-peptidase-like 2B

Inhibition of intramembrane aspartyl protease activity (preclinical inhibitors target substrate cleavage), Modulation of immune signaling via TNF-alpha processing