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J Biol Chem. 2014 Jul 11;289(28):19670-80. doi: 10.1074/jbc.M113.515700. Epub 2014 May 28.

Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a).

Author information

1
From the Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853.
2
From the Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853 fh87@cornell.edu.

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.

KEYWORDS:

Frontotemporal Lobar Degeneration; Intramembrane Proteolysis; Lysosomal Glycoprotein; Lysosome; Neurodegenerative Disease; SPPL2a; Shedding; TMEM106B

PMID:
24872421
PMCID:
PMC4094077
DOI:
10.1074/jbc.M113.515700
[Indexed for MEDLINE]
Free PMC Article

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