title: Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a).
abstract: The sequential processing of single pass transmembrane proteins via ectodomain shedding followed by intramembrane proteolysis is involved in a wide variety of signaling processes, as well as maintenance of membrane protein homeostasis. Here we report that the recently identified frontotemporal lobar degeneration risk factor TMEM106B undergoes regulated intramembrane proteolysis. We demonstrate that TMEM106B is readily processed to an N-terminal fragment containing the transmembrane and intracellular domains, and this processing is dependent on the activities of lysosomal proteases. The N-terminal fragment is further processed into a small, rapidly degraded intracellular domain. The GxGD aspartyl proteases SPPL2a and, to a lesser extent, SPPL2b are responsible for this intramembrane cleavage event. Additionally, the TMEM106B paralog TMEM106A is also lysosomally localized; however, it is not a specific substrate of SPPL2a or SPPL2b. Our data add to the growing list of proteins that undergo intramembrane proteolysis and may shed light on the regulation of the frontotemporal lobar degeneration risk factor TMEM106B.
authors.affiliation: From the Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Brady
authors.affiliation: From the Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853.
authors.forename: Xiaolai
authors.initials: X
authors.lastname: Zhou
authors.affiliation: From the Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853 fh87@cornell.edu.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Hu
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D012307:Risk Factors
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C556915:TMEM106B protein, human; D016282:Aspartic Acid Endopeptidases; C524670:SPPL2a protein, human; C568855:SPPL2a protein, mouse
keywords: Frontotemporal Lobar Degeneration; Intramembrane Proteolysis; Lysosomal Glycoprotein; Lysosome; Neurodegenerative Disease; SPPL2a; Shedding; TMEM106B