Regulated Intramembrane Proteolysis of the Frontotemporal Lobar Degeneration Risk Factor, TMEM106B, by Signal Peptide Peptidase-like 2a (SPPL2a)

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...

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Bibliographic Details
Published in:The Journal of biological chemistry 2014-07, Vol.289 (28), p.19670-19680
Main Authors: Brady, Owen A., Zhou, Xiaolai, Hu, Fenghua
Format: Article
Language:English
Subjects:
Animals
Aspartic Acid Endopeptidases - genetics
Aspartic Acid Endopeptidases - metabolism
Cell Membrane - genetics
Cell Membrane - metabolism
Frontotemporal Lobar Degeneration
HEK293 Cells
Humans
Intramembrane Proteolysis
Lysosomal Glycoprotein
Lysosome
Lysosomes - genetics
Lysosomes - metabolism
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Molecular Bases of Disease
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurodegenerative Disease
Protein Structure, Tertiary
Proteolysis
Risk Factors
Shedding
SPPL2a
TMEM106B
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Summary: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. Background: TMEM106B polymorphisms are associated with some forms of dementia. Results: A pathway for the sequential processing of TMEM106B on the lysosome membrane has been identified. Conclusion: TMEM106B undergoes processing via removal of its lumenal domain, followed by intramembrane cleavage by the protease SPPL2a. Significance: This may represent a mechanism for regulation of TMEM106B levels.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.515700