ArticleThe Journal of biological chemistry2014
Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a).
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 49 citations in OpenAlex.
- Protective TMEM106B-rs3173615 delays age at onset in GRN mutation carriers.Molecular psychiatry · 2026Article
- MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer's Disease.bioRxiv : the preprint server for biology · 2026Article
- Structural insights into human signal peptide peptidase.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Divergent and convergent TMEM106B pathology in murine models of neurodegeneration and human disease.Acta neuropathologica communications · 2025Article
- The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
- Accumulation of TMEM106B C-terminal fragments in Niemann-Pick type C disease.Journal of neuropathology and experimental neurology · 2024Article
- Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer's disease.Cell reports. Medicine · 2024Article
- TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy.bioRxiv : the preprint server for biology · 2024Article
- Physiological and pathological functions of TMEM106B in neurodegenerative diseases.Cellular and molecular life sciences : CMLS · 2024Review
- The endolysosomal pathway and ALS/FTD.Trends in neurosciences · 2023Review
- C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes.Brain : a journal of neurology · 2023Article
- TMEM106B aggregation in neurodegenerative diseases: linking genetics to function.Molecular neurodegeneration · 2023Review
- Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease.Acta neuropathologica · 2022Review
- Cell-type-specific cis-eQTLs in eight human brain cell types identify novel risk genes for psychiatric and neurological disorders.Nature neuroscience · 2022Article
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- Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.Neurobiology of disease · 2021Review
- Systematic detection of functional proteoform groups from bottom-up proteomic datasets.Nature communications · 2021Article
- Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes.Nature communications · 2021Article
- Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders.Acta neuropathologica · 2021Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.