Affinage

TMEM106B

Transmembrane protein 106B · UniProt Q9NUM4

Length
274 aa
Mass
31.1 kDa
Annotated
2026-06-13
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM106B is a type II integral membrane protein resident in late endosomes and lysosomes that governs lysosomal morphology, acidification, positioning, and degradative capacity, thereby acting as a central regulator of endolysosomal and autophagic homeostasis in neurons, glia, and other cell types (PMID:22511793, PMID:22895706, PMID:27126638). Its highly glycosylated luminal domain faces the lysosomal lumen, while its intrinsically disordered cytoplasmic N-terminus enables transient interactions; protein levels are tuned by lysosomal activity and by the miR-132/miR-212 cluster (PMID:22511793, PMID:30332472, PMID:22895706). TMEM106B promotes lysosomal acidification by binding the vacuolar-ATPase accessory protein AP1 and supporting V-ATPase subunit levels, and its loss reduces acidification and normalizes the elevated lysosomal enzyme and protein levels seen in progranulin-null neurons—Tmem106b deletion rescues FTLD-related phenotypes in Grn-/- mice (PMID:28728022). It controls anterograde lysosomal transport along axons and dendrites through interaction with MAP6 and through Arl8b-dependent positioning, such that its loss causes retrograde transport bias, perinuclear/juxtanuclear lysosome clustering, and a block in autophagosome-to-autolysosome maturation (PMID:24357581, PMID:32160553, PMID:36619668). TMEM106B regulates lysosomal protease and lipid metabolism via physical interactions with cathepsin D and galactosylceramidase, controlling myelin lipid (galactosylceramide/sulfatide) levels and oligodendrocyte function, and it sustains microglial lysosomal function and TREM2 levels (PMID:32572497, PMID:39237682, PMID:37146150). The luminal domain is cleaved by lysosomal cysteine proteases to generate a C-terminal fragment (residues ~120–254) that forms age-dependent amyloid fibrils with three distinct cryo-EM folds across diverse neurodegenerative diseases—these fibrils, rather than TDP-43, constitute the filaments previously attributed to FTLD-TDP brains (PMID:39709600, PMID:35344985, PMID:35344984, PMID:35247328). Both gain and loss of TMEM106B are pathogenic: overexpression causes lysosomal vacuolation, impaired acidification, cytotoxicity, and neuronal dysfunction, while loss accelerates tau and TDP-43 proteinopathy, and the protective T185S coding variant acts downstream of tau aggregation to preserve neuronal health (PMID:27126638, PMID:40269985, PMID:38526616, PMID:34152475). Independently of its lysosomal role, TMEM106B serves as an ACE2-independent entry receptor for SARS-CoV-2, with its luminal domain directly engaging the spike receptor-binding motif (PMID:37421949, PMID:33686287).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2012 High

    Establishing that TMEM106B is a glycosylated type II membrane protein resident in late endosomes/lysosomes whose levels are set by lysosomal activity defined the compartment in which all subsequent function would be interpreted.

    Evidence Differential membrane extraction, N-glycosylation mutagenesis, fractionation, and V-ATPase inhibitor treatment

    PMID:22511793

    Open questions at the time
    • Topology established but luminal-domain function not defined
    • No partners identified at this stage
  2. 2012 High

    Demonstrating that TMEM106B overexpression enlarges and de-acidifies lysosomes, impairs M6PR trafficking and cargo degradation, and raises progranulin levels linked the protein mechanistically to lysosomal degradative function and the FTLD progranulin axis.

    Evidence Overexpression in neurons/cells, lysosomal pH and trafficking assays, progranulin ELISA, miRNA reporter validation

    PMID:22895706 PMID:23136129

    Open questions at the time
    • Gain-of-function phenotype; physiological loss-of-function role unresolved
    • Direct molecular cause of acidification defect not identified
  3. 2013 High

    Identifying the MAP6 interaction and reciprocal epistasis established that TMEM106B drives anterograde lysosomal transport required for dendritic arborization, moving the protein from a static lysosomal marker to a transport regulator.

    Evidence shRNA knockdown in primary neurons, live lysosome imaging, Co-IP, dominant-negative RILP rescue, double knockdown

    PMID:24357581

    Open questions at the time
    • Direct biochemical bridge between luminal TMEM106B and cytoplasmic motor machinery not resolved
    • Whether MAP6 binding is direct vs. complex-mediated unclear
  4. 2013 Medium

    Showing that the risk T185 isoform is more stable than the protective S185 isoform provided a candidate molecular basis for the disease-associated coding variant.

    Evidence Cycloheximide chase stability assay, isoform-specific overexpression, progranulin ELISA

    PMID:23742080

    Open questions at the time
    • Stability difference correlated with but not proven to cause disease risk
    • Glycosylation mechanism at N183 inferred, not directly demonstrated
  5. 2014 High

    Defining regulated intramembrane proteolysis by lysosomal proteases and SPPL2a/SPPL2b established a processing pathway for TMEM106B and distinguished it from the non-substrate paralog TMEM106A.

    Evidence SPPL2a/SPPL2b knockdown/overexpression, protease inhibitors, fragment western blots

    PMID:24872421

    Open questions at the time
    • Functional consequence of the released intracellular fragment unknown
    • Relationship of this processing to fibril-forming luminal fragment not yet connected
  6. 2016 High

    Mapping the lysosomal sorting motif requirement and C9orf72 dependence of the overexpression phenotype tied TMEM106B-driven lysosomal toxicity to specific trafficking determinants and a known FTD/ALS gene.

    Evidence Overexpression in multiple cell types, sorting motif mutagenesis, lysosomal pH/degradation/cytotoxicity assays, C9orf72 siRNA epistasis

    PMID:27126638

    Open questions at the time
    • Molecular nature of C9orf72 dependence not defined
    • ESCRT/CHMP2B association reported separately but mechanistically incomplete
  7. 2017 High

    Identifying the V-ATPase accessory protein AP1 as a binding partner and showing Tmem106b deletion rescues Grn-/- lysosomal and behavioral phenotypes established the molecular basis of TMEM106B-dependent acidification and its in vivo modifier role in FTLD.

    Evidence Co-IP, lysosomal pH measurement, transcriptomics/proteomics in Grn-/- × Tmem106b-/- mice, behavioral and retinal assessment

    PMID:28728022

    Open questions at the time
    • Direct stoichiometry/assembly with V-ATPase not resolved
    • Whether AP1 binding is luminal or cytoplasmic not specified
  8. 2018 High

    A series of studies extended TMEM106B function to autophagic flux (CHMP2B/ESCRT context), VPS4-dependent endolysosome trafficking, cancer metastasis via TFEB-driven lysosomal cathepsin secretion, and defined its cytoplasmic domain as intrinsically disordered, broadening its mechanistic reach.

    Evidence Co-IP, CHMP2B/VPS4 epistasis, in vivo metastasis and cathepsin/exocytosis assays with TFEB knockdown, CD/NMR spectroscopy

    PMID:26651479 PMID:30013069 PMID:30332472 PMID:30496365

    Open questions at the time
    • How disordered cytoplasmic domain selects diverse partners undefined
    • Direct vs. indirect role in TFEB/CLEAR regulation unresolved
  9. 2020 High

    Knockout mice revealed that TMEM106B mediates anterograde axonal lysosome transport and axon-initial-segment sorting and physically interacts with cathepsin D to regulate myelination, linking lysosomal positioning and protease control to neuronal and oligodendrocyte integrity.

    Evidence TMEM106B-deficient mice and Oli-neu cells, axonal transport imaging, lipofuscin/autophagosome staining, motor testing, Co-IP with cathepsin D, D252N mutant analysis

    PMID:32160553 PMID:32572497

    Open questions at the time
    • Mechanism by which D252N inverts the gain-of-function phenotype not fully resolved
    • Direct vs. regulatory role on cathepsin D activity unclear
  10. 2021 High

    A genome-wide CRISPR screen identified TMEM106B as required for SARS-CoV-2 infection and entry, revealing a function entirely distinct from its lysosomal role.

    Evidence Genome-wide CRISPR knockout screen, infection of cell lines/primary lung cells, overexpression/pseudovirus assays

    PMID:33686287

    Open questions at the time
    • Mechanism of entry (receptor vs. cofactor) not yet defined in this study
    • Relationship to lysosomal residence unclear
  11. 2021 Low

    Computational analysis predicting a LEA-2 lipid-binding fold in the luminal domain offered a structural hypothesis for a lipid-handling function.

    Evidence PSI-BLAST, HMMER, HHpred, trRosetta structure prediction

    PMID:34347309

    Open questions at the time
    • Computational prediction only; no experimental validation of lipid transfer activity
    • Predicted fold not yet reconciled with experimental luminal structures
  12. 2021 Medium

    Partial knockdown mimicking risk-allele expression increased and insolubilized TDP-43 cytoplasmic aggregates, providing causal support for TMEM106B as a modifier of TDP-43 proteinopathy.

    Evidence Inducible TDP-43 mislocalization cell system, siRNA partial knockdown, aggregate quantification, filter-trap solubility assay

    PMID:34152475

    Open questions at the time
    • Single cell-based system; in vivo confirmation absent here
    • Mechanism connecting lysosomal function to TDP-43 aggregation not defined
  13. 2022 High

    Cryo-EM determination of TMEM106B amyloid fibrils from human brain established that the C-terminal luminal fragment, not TDP-43, forms the filaments in FTLD-TDP and across diverse neurodegenerative diseases and aged brains, overturning a prior assumption and defining an age-dependent amyloid.

    Evidence Cryo-EM structure determination across multiple diseases/subjects, sarkosyl fractionation, immunogold for TDP-43, mass spectrometry

    PMID:35247328 PMID:35344984 PMID:35344985

    Open questions at the time
    • Whether fibrils are pathogenic, protective, or bystander not resolved
    • No clear fold–disease relationship established
    • Trigger of age-dependent fibril formation unknown
  14. 2022 High

    Demonstrating an Arl8b- and Rab7A-dependent block in autophagosome-to-autolysosome maturation upon TMEM106B loss placed the protein at a defined step of autophagy and lysosomal positioning, with Arl8b restoration rescuing the defect.

    Evidence siRNA knockdown, tandem LC3 maturation reporter, lysosomal pH and cathepsin assays, Rab7A epistasis, Arl8b overexpression rescue

    PMID:36619668

    Open questions at the time
    • Direct interaction with Arl8b vs. indirect regulation not established
    • Link between maturation block and DPR accumulation mechanism incomplete
  15. 2023 High

    Structural determination of the TMEM106B luminal domain–spike complex established TMEM106B as a bona fide ACE2-independent SARS-CoV-2 entry receptor engaging the spike receptor-binding motif, with neutralizing antibody and syncytium evidence.

    Evidence X-ray crystallography, cryo-EM, HDX-MS, pseudovirus entry, monoclonal antibody blocking, syncytium assay

    PMID:37421949

    Open questions at the time
    • In vivo relevance to COVID-19 pathology not established here
    • Interplay with ACE2-positive cells unclear
  16. 2023 High

    Microglial-specific knockout showed TMEM106B sustains microglial lysosomal function and TREM2 levels and supports proliferation/survival during demyelination, extending its role into neuroimmune lysosomal biology.

    Evidence Conditional microglial knockout mice, demyelination model, proliferation/apoptosis assays, lysosomal pH and enzyme activity, TREM2 western blot

    PMID:37146150

    Open questions at the time
    • Mechanism linking TMEM106B to TREM2 stability not defined
    • Direct vs. lysosome-mediated effect on TREM2 unclear
  17. 2024 High

    Identifying lysosomal cysteine proteases as the enzymes that cleave and trim the luminal domain to the fibril-forming fragment connected physiological proteolysis to amyloid generation.

    Evidence Cysteine protease inhibitors, luminal-domain antibody, western blots in KO vs WT cells/mice, fibril detection in human autopsy tissue

    PMID:39709600

    Open questions at the time
    • Specific protease identity at species level not narrowed
    • Why cleavage products become amyloidogenic with age unresolved
  18. 2024 High

    The galactosylceramidase interaction and lipidomic consequences of TMEM106B loss established that TMEM106B regulates myelin lipid metabolism by modulating a lysosomal lipid-degrading enzyme.

    Evidence Co-IP, galactosylceramidase activity assay, brain lipidomics in TMEM106B-deficient mice

    PMID:39237682

    Open questions at the time
    • Whether TMEM106B inhibits or scaffolds galactosylceramidase mechanistically unclear
    • Connection to predicted luminal lipid-binding fold not tested
  19. 2024 High

    Crossing TMEM106B knockout and T185S knock-in alleles into tauopathy models demonstrated that loss accelerates tau pathology and neurodegeneration while the protective coding variant preserves neuronal health downstream of tau aggregation, proving the variant is functionally relevant in vivo.

    Evidence Tmem106b KO and T186S knock-in × P301S/PS19 tau mice, behavioral/motor testing, tau pathology and synaptic/neurodegeneration readouts

    PMID:38526616 PMID:38526799

    Open questions at the time
    • Molecular pathway by which TMEM106B limits tau-driven degeneration not fully defined
    • How T185S acts downstream of tau aggregation mechanistically unclear
  20. 2025 High

    A transgenic overexpression mouse model established that elevated TMEM106B levels alone are sufficient to cause lysosomal dysfunction, synaptic/transcriptomic decline, and neuronal loss, confirming pathogenic gain of function in vivo.

    Evidence Cre-inducible transgenic mice, electron microscopy, electrophysiology, behavior, bulk RNA-seq

    PMID:40269985

    Open questions at the time
    • Whether overexpression toxicity proceeds via fibril formation untested here
    • Relationship of gain-of-function to loss-of-function phenotypes unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether the age-dependent amyloid fibrils are pathogenic, protective, or incidental, and how a single protein reconciles opposing gain- and loss-of-function disease mechanisms, remains the central unresolved question.
  • No causal demonstration that fibrils drive neurodegeneration
  • No unified model linking lysosomal dysfunction, fibril formation, and the protective coding variant
  • Physiological function of the predicted luminal lipid-binding fold experimentally untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0005198 structural molecule activity 3 GO:0001618 virus receptor activity 2
Localization
GO:0005764 lysosome 5 GO:0005768 endosome 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1430728 Metabolism 2 R-HSA-9612973 Autophagy 2
Partners
ARL8BATP6AP1CHMP2BCTSDGALCMAP6RAB7A

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 TMEM106B is a type II integral membrane protein with a highly glycosylated luminal domain. Glycosylation (partially required for transport beyond the ER) was established by differential membrane extraction and sequential mutagenesis of N-glycosylation sites. Endogenous and overexpressed TMEM106B localizes to late endosomes and lysosomes. Inhibition of vacuolar H(+)-ATPase significantly increased TMEM106B protein levels. Differential membrane extraction, sequential N-glycosylation site mutagenesis, subcellular fractionation, immunofluorescence, vacuolar H(+)-ATPase inhibitor treatment The Journal of biological chemistry High 22511793
2012 TMEM106B overexpression induces enlargement and poor acidification of endo-lysosomes, impairs mannose-6-phosphate receptor trafficking, and increases intracellular progranulin levels. Endogenous neuronal TMEM106B co-localizes with progranulin in late endo-lysosomes. miR-132 and miR-212 repress TMEM106B expression through shared binding sites in its 3'UTR. TMEM106B overexpression in neurons, lysosomal pH assay, mannose-6-phosphate receptor trafficking assay, co-localization by immunofluorescence, microRNA binding site validation (luciferase reporter/empirical corroboration), microarray miRNA screen The Journal of neuroscience : the official journal of the Society for Neuroscience High 22895706
2012 TMEM106B overexpression in cells localizes to late endosome/lysosome compartments, induces morphological changes in lysosomes, delays degradation of endocytic cargoes, and elevates intracellular progranulin levels, likely by attenuating lysosomal degradation of progranulin. TMEM106B protein levels are regulated by lysosomal activity. Ectopic TMEM106B expression, lysosomal inhibitor treatment, endocytic cargo degradation assay, progranulin level measurement by ELISA/western blot, immunofluorescence co-localization Human molecular genetics High 23136129
2013 TMEM106B knockdown in primary neurons impairs lysosomal trafficking, blunts dendritic arborization, and increases retrograde lysosomal transport in dendrites. TMEM106B physically interacts with microtubule-associated protein 6 (MAP6). MAP6 overexpression phenocopies TMEM106B knockdown (reduced dendritic branching), and MAP6 knockdown fully rescues the dendritic phenotype of TMEM106B knockdown, consistent with a functional interaction. Expressing dominant-negative RILP to enhance anterograde lysosomal transport also rescues dendrite loss in TMEM106B knockdown neurons. shRNA knockdown in primary neurons, live-cell lysosome trafficking imaging, Co-immunoprecipitation (TMEM106B–MAP6), dendritic arborization morphometry, dominant-negative RILP expression, epistasis by double knockdown The EMBO journal High 24357581
2013 The TMEM106B coding variant T185S (rs3173615) affects protein stability: the T185 (risk) isoform is present at higher protein levels than S185 (protective) isoform. Cycloheximide chase experiments show S185 degrades faster than T185, potentially due to differences in N-glycosylation at residue N183. Both isoforms have similar effects on progranulin protein levels when overexpressed. Cycloheximide chase protein stability assay, TMEM106B-specific antibody characterization, ELISA for progranulin, overexpression of T185 and S185 variants Journal of neurochemistry Medium 23742080
2014 TMEM106B undergoes regulated intramembrane proteolysis: it is processed by lysosomal proteases to generate an N-terminal fragment containing the transmembrane and intracellular domains, which is then further cleaved into a small, rapidly degraded intracellular domain by the GxGD aspartyl proteases SPPL2a and (to a lesser extent) SPPL2b. The TMEM106B paralog TMEM106A localizes to lysosomes but is not a substrate of SPPL2a or SPPL2b. Overexpression and inhibitor studies, SPPL2a/SPPL2b knockdown and overexpression, fragment detection by western blot, lysosomal protease inhibitor treatment The Journal of biological chemistry High 24872421
2015 TMEM106B associates with CHMP2B-positive structures (ESCRT-associated), suggesting involvement in ESCRT pathways. The T185 risk variant is more strongly localized to Rab7-positive late endosomes and more associated with CHMP2B compared to the S185 protective variant. T185 slightly reduces autophagic flux and enhances EGFR accumulation and neurotoxicity caused by mutant CHMP2B(Intron5) compared to S185. Co-immunoprecipitation (TMEM106B–CHMP2B), immunofluorescence co-localization with Rab5/Rab7, autophagic flux assay, EGFR accumulation assay, neurotoxicity assay Molecular brain Medium 26651479
2016 Increased TMEM106B expression causes a lysosomal vacuolar phenotype in multiple cell types including neurons, impairs lysosomal acidification and degradative function, and increases cytotoxicity. A lysosomal sorting motif in TMEM106B is required for these effects; abrogation of lysosomal sorting rescues them. TMEM106B-induced lysosomal defects are dependent on C9orf72, as C9orf72 knockdown rescues these defects. TMEM106B overexpression in multiple cell lines and neurons, lysosomal pH assay, degradative function assay, cytotoxicity assay, lysosomal sorting motif mutagenesis, C9orf72 siRNA knockdown epistasis Human molecular genetics High 27126638
2017 TMEM106B binds vacuolar-ATPase accessory protein 1 (AP1). TMEM106B deficiency reduces vacuolar-ATPase AP1 and V0 subunits, impairing lysosomal acidification and normalizing elevated lysosomal enzyme levels seen in progranulin-null neurons. In Grn−/− mice, Tmem106b deletion normalizes lysosomal protein levels and rescues FTLD-related behavioral abnormalities and retinal degeneration. Co-immunoprecipitation (TMEM106B–vacuolar-ATPase AP1), lysosomal pH measurement, transcriptomic and proteomic analysis of Grn−/− and Tmem106b−/− mice, behavioral testing, retinal degeneration assessment Neuron High 28728022
2018 TMEM106B knockdown rescues impaired endolysosomal trafficking and increased dendritic branching caused by mutant CHMP2B in neurons. Mechanistically, mutant CHMP2B stably incorporates onto neuronal endolysosomes and prevents their dendritic trafficking due to failure to recruit VPS4 ATPase (required for CHMP2B release). Antisense oligonucleotides (ASOs) targeting TMEM106B restore endosomal health in this context. ASO-mediated TMEM106B knockdown, live-cell endolysosome trafficking imaging in neurons, VPS4 recruitment assay, dendritic branching morphometry Brain : a journal of neurology High 30496365
2018 TMEM106B drives lung cancer metastasis by promoting synthesis of enlarged lysosomes laden with elevated active cathepsins. In a TFEB-dependent manner, TMEM106B modulates lysosomal gene expression through the CLEAR pathway. TMEM106B-induced lysosomes undergo calcium-dependent exocytosis, releasing active cathepsins necessary for cancer cell invasion; pharmacological cathepsin inhibition prevents TMEM106B-mediated metastasis in vivo. Ectopic TMEM106B expression, in vivo metastasis assay (gain-of-function screen), lysosome size/number quantification, cathepsin activity assay, TFEB dependency (siRNA knockdown), calcium-dependent exocytosis assay, pharmacological cathepsin inhibition Nature communications High 30013069
2018 The TMEM106B cytoplasmic domain (N-terminal, cytoplasmic-facing) is intrinsically disordered, with no well-defined tertiary structure, as demonstrated by CD and NMR spectroscopy. Several segments have dynamic/nascent secondary structures and relatively restricted backbone motions (ps-ns timescale), potentially allowing transient interactions with diverse partners. CD spectroscopy, multi-dimensional NMR spectroscopy ({1H}-15N steady-state NOE, chemical shift analysis) PloS one High 30332472
2020 TMEM106B deficiency in mice leads to enlarged LAMP1-positive vacuoles accumulating at the distal end and within the axon initial segment of motoneurons, increased retrograde axonal transport of lysosomes, lipofuscin accumulation, and autophagosome accumulation, resulting in impaired motor performance. TMEM106B mediates anterograde axonal transport of LAMP1-positive organelles and axonal sorting at the initial segment. TMEM106B-deficient mouse model, LAMP1 immunofluorescence/confocal imaging, live-cell axonal transport quantification, lipofuscin staining, autophagosome staining, motor behavior testing (facial-nerve-dependent assay) Cell reports High 32160553
2020 TMEM106B deficiency in mice causes myelination defects with significant reduction of proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) levels. TMEM106B localizes to lysosomes in oligodendrocytes, physically interacts with lysosomal protease cathepsin D, and is required to maintain proper cathepsin D levels. TMEM106B deficiency causes lysosome clustering in the perinuclear region and decreased lysosome exocytosis and cell-surface PLP levels. The disease-linked D252N mutation abolishes lysosome enlargement and acidification induced by wild-type TMEM106B overexpression, and instead promotes lysosome perinuclear clustering similar to TMEM106B deficiency. TMEM106B-deficient mice and Oli-neu cell line, immunofluorescence, western blot (PLP, MOG, cathepsin D), Co-immunoprecipitation (TMEM106B–cathepsin D), lysosome exocytosis assay, cell-surface PLP measurement, D252N mutant overexpression, lysosomal pH assay Brain : a journal of neurology High 32572497
2021 TMEM106B is required for SARS-CoV-2 infection of human cell lines and primary lung cells. TMEM106B overexpression enhances SARS-CoV-2 infection and pseudovirus infection, implicating a role in viral entry. Identified by genome-wide CRISPR functional screen. Genome-wide CRISPR knockout screen, SARS-CoV-2 infection assay (cell lines and primary lung cells), TMEM106B overexpression/pseudovirus infection assay Nature genetics High 33686287
2021 TMEM106B is predicted, by sequence analysis using PSI-BLAST, HMMER, HHpred, and trRosetta, to contain a late embryogenesis abundant-2 (LEA-2) domain superfamily fold in its luminal domain, which has a conserved lipid-binding groove, suggesting TMEM106B may function as a lipid transfer protein in the lumen of late endocytic organelles. Computational sequence analysis (PSI-BLAST, HMMER, HHpred, trRosetta structure prediction) Proteins Low 34347309
2022 Residues 120–254 of the C-terminal luminal domain of TMEM106B form amyloid filaments in human brains with diverse neurodegenerative diseases (tauopathies, amyloid-β amyloidoses, synucleinopathies, TDP-43 proteinopathies) and in neurologically normal aged individuals. Three distinct TMEM106B fibril folds were identified, with no clear relationship between fold and disease type. TMEM106B filaments correlate with a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions and form in an age-dependent manner. Cryo-electron microscopy structure determination, sarkosyl fractionation, C-terminal-specific antibody immunodetection, postmortem human brain analysis Nature High 35344985
2022 Amyloid fibrils extracted from FTLD-TDP brains (four FTLD-TDP subclasses) are composed of a 135-residue C-terminal fragment of TMEM106B (not TDP-43 as previously assumed). TDP-43 is present as non-fibrillar aggregates detected by immunogold labelling. TMEM106B fibril structure was solved by cryo-EM. Cryo-EM structure determination of amyloid fibrils from postmortem FTLD-TDP brain, immunogold labelling for TDP-43, biochemical extraction of fibrils Nature High 35344984
2022 A 135-amino acid C-terminal fragment of TMEM106B forms amyloid fibrils (structure solved at 2.7 Å resolution) common to FTLD-TDP, progressive supranuclear palsy, and dementia with Lewy bodies. The fibril structure is homotypic and consistent across distinct neurodegenerative diseases. Cryo-electron microscopy (2.7 Å resolution), mass spectrometry, postmortem human brain tissue from multiple diseases Cell High 35247328
2022 TMEM106B loss causes a block late in autophagy by disrupting autophagosome-to-autolysosome maturation, coinciding with impaired lysosomal acidification, reduced cathepsin activity, and juxtanuclear lysosome clustering. Lysosomal clustering requires Rab7A and is associated with reduced Arl8b-mediated anterograde lysosomal transport. Restoring Arl8b activity in TMEM106B-deficient cells rescues lysosome distribution, autophagy, and DPR protein accumulation. TMEM106B siRNA knockdown, autophagosome–autolysosome maturation assay (tandem fluorescent LC3 reporter), lysosomal pH measurement, cathepsin activity assay, live-cell lysosome distribution imaging, Rab7A siRNA epistasis, Arl8b overexpression rescue Frontiers in cellular neuroscience High 36619668
2023 TMEM106B serves as an ACE2-independent receptor for SARS-CoV-2 entry into ACE2-negative cells. The luminal domain (LD) of TMEM106B directly engages the receptor-binding motif of SARS-CoV-2 spike (established by X-ray crystallography, cryo-EM, and HDX-MS). Spike substitution E484D enhances TMEM106B binding and TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies block SARS-CoV-2 infection. TMEM106B also promotes spike-mediated syncytium formation, suggesting a role in viral membrane fusion. TMEM106B acts cooperatively with heparan sulfate. X-ray crystallography, cryo-EM, hydrogen-deuterium exchange mass spectrometry (HDX-MS), pseudovirus entry assay, monoclonal antibody blocking, syncytium formation assay, ACE2-negative cell infection assay Cell High 37421949
2023 TMEM106B deficiency in mice reduces microglial proliferation and activation and increases microglial apoptosis in response to demyelination. TMEM106B-deficient microglia have increased lysosomal pH and decreased lysosomal enzyme activities. TMEM106B loss causes significant decrease in TREM2 protein levels in microglia. Microglial-specific TMEM106B ablation recapitulates these phenotypes and causes myelination defects. Conditional (microglial-specific) TMEM106B knockout mice, demyelination model, microglial proliferation/apoptosis assays, lysosomal pH measurement, lysosomal enzyme activity assay, TREM2 western blot, myelination assessment Science advances High 37146150
2024 The luminal domain of TMEM106B is cleaved by multiple lysosomal cysteine-type proteases to generate the C-terminal fragment capable of fibril formation. Cysteine-type proteases also perform additional C-terminal trimming of this fragment. Fibrillar TMEM106B was detected in human autopsy material. These cleavage events occur under physiological conditions in cellular models and mouse models. Cysteine protease inhibitors, custom antibody against luminal domain, western blot in knockout and wild-type cellular/mouse models, immunodetection of fibrils in human autopsy material Cell reports High 39709600
2024 TMEM106B physically interacts with galactosylceramidase (co-immunoprecipitation). TMEM106B deficiency significantly increases galactosylceramidase activity and decreases levels of galactosylceramide and sulfatide (major myelin lipids) in mouse brain, establishing that TMEM106B regulates myelin lipid metabolism through modulation of galactosylceramidase. Lipidomic analysis of TMEM106B-deficient mouse brain, co-immunoprecipitation (TMEM106B–galactosylceramidase), galactosylceramidase activity assay Communications biology High 39237682
2024 TMEM106B deletion in a tauopathy mouse model (P301S tau) accelerates cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. In contrast, the T185S (T186S in mouse) coding variant protects against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology itself, demonstrating the coding variant is functionally relevant and acts downstream of tau aggregation. TMEM106B knockout and T186S knock-in mice crossed with P301S tau transgenic model, behavioral testing (cognitive, motor), tau pathology quantification, synaptic marker analysis, neurodegeneration assessment, transcriptomic correlation with human AD Acta neuropathologica High 38526616
2024 Loss of TMEM106B enhances accumulation of pathological tau (especially in neuronal soma in hippocampus) and causes severe neuronal loss, cytoskeletal abnormalities, increased autophagy-lysosome dysfunction, and glial activation in PS19 tau transgenic mice, indicating TMEM106B is required to limit tau pathology progression. Tmem106b−/− × PS19 tau transgenic cross, immunofluorescence for phospho-tau, neuronal count, cytoskeletal markers, autophagy-lysosome markers, glial activation markers Acta neuropathologica High 38526799
2021 Partial knockdown of TMEM106B (to levels expected in rs1990622 C-allele carriers) in an inducible TDP-43 mislocalization cell system leads to more TDP-43 cytoplasmic aggregates that are more insoluble, supporting a causal role for TMEM106B in modifying TDP-43 proteinopathy. Inducible TDP-43 mislocalization cell system, TMEM106B siRNA partial knockdown, TDP-43 aggregate quantification, solubility fractionation (filter trap assay) Acta neuropathologica Medium 34152475
2025 Transgenic mice overexpressing human TMEM106B (4–8-fold increase) develop lysosomal dysfunction, age-related downregulation of genes associated with neuronal plasticity and memory, altered synaptic signaling, anxiety-like phenotype, and mild hippocampal neuronal loss, establishing that elevated TMEM106B levels are sufficient to impair lysosomal and neuronal health. Cre-inducible transgenic mouse model, transmission electron microscopy, immunostaining, behavioral testing, electrophysiology, bulk RNA sequencing Molecular neurodegeneration High 40269985

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 219 21178100
2012 TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. The Journal of neuroscience : the official journal of the Society for Neuroscience 203 22895706
2021 Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2. Nature genetics 191 33686287
2012 The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Human molecular genetics 172 23136129
2022 Age-dependent formation of TMEM106B amyloid filaments in human brains. Nature 166 35344985
2011 Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Archives of neurology 150 21220649
2013 The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. The EMBO journal 147 24357581
2017 Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. Neuron 145 28728022
2022 Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43. Nature 140 35344984
2014 TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta neuropathologica 137 24385136
2012 Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. The Journal of biological chemistry 136 22511793
2022 Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. Cell 130 35247328
2014 TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta neuropathologica 125 24442578
2023 TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry. Cell 116 37421949
2018 TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins. Nature communications 116 30013069
2011 TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain : a journal of neurology 112 21354975
2017 Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes. Cell systems 109 28330615
2010 Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta neuropathologica 107 21104415
2013 TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. Journal of neurochemistry 102 23742080
2016 What we know about TMEM106B in neurodegeneration. Acta neuropathologica 94 27543298
2021 Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders. Acta neuropathologica 88 33386471
2020 Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice. EMBO reports 86 32852886
2015 The TMEM106B locus and TDP-43 pathology in older persons without FTLD. Neurology 81 25653292
2021 rs1990622 variant associates with Alzheimer's disease and regulates TMEM106B expression in human brain tissues. BMC medicine 77 33461566
2017 A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain : a journal of neurology 74 29186371
2019 The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion. Acta neuropathologica 67 31456032
2020 The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons. Cell reports 66 32160553
2015 Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology. Journal of neuropathology and experimental neurology 66 25470345
2016 Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Human molecular genetics 61 27126638
2022 Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging. Acta neuropathologica 59 36527486
2020 Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice. EMBO reports 55 32929860
2020 Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies. Brain : a journal of neurology 52 32504082
2017 Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study. Brain : a journal of neurology 52 28460069
2018 Variation in TMEM106B in chronic traumatic encephalopathy. Acta neuropathologica communications 51 30390709
2020 Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice. EMBO reports 50 32761777
2021 Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study. Acta neuropathologica communications 48 34526147
2020 A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination. Brain : a journal of neurology 47 32572497
2014 Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). The Journal of biological chemistry 43 24872421
2019 Long noncoding MAGI2-AS3 promotes colorectal cancer progression through regulating miR-3163/TMEM106B axis. Journal of cellular physiology 42 31709544
2017 Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency. Acta neuropathologica communications 42 28126008
2014 TMEM106B expression is reduced in Alzheimer's disease brains. Alzheimer's research & therapy 40 24684749
2014 Defining the association of TMEM106B variants among frontotemporal lobar degeneration patients with GRN mutations and C9orf72 repeat expansions. Neurobiology of aging 39 25085782
2014 Effect of TMEM106B polymorphism on functional network connectivity in asymptomatic GRN mutation carriers. JAMA neurology 38 24343233
2018 Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown. Brain : a journal of neurology 35 30496365
2015 TMEM106B, a frontotemporal lobar dementia (FTLD) modifier, associates with FTD-3-linked CHMP2B, a complex of ESCRT-III. Molecular brain 35 26651479
2023 The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus. Molecular neurodegeneration 34 37726834
2013 Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain. Acta neuropathologica communications 34 24252750
2024 TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia. Science translational medicine 33 38232138
2015 Identification of a novel TMEM106B-ROS1 fusion variant in lung adenocarcinoma by comprehensive genomic profiling. Lung cancer (Amsterdam, Netherlands) 33 25851827
2023 TMEM106B aggregation in neurodegenerative diseases: linking genetics to function. Molecular neurodegeneration 32 37563705
2017 A novel, potentially targetable TMEM106B-BRAF fusion in pleomorphic xanthoastrocytoma. Cold Spring Harbor molecular case studies 29 28299358
2022 Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease. Acta neuropathologica 28 36056242
2018 Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency. Molecular neurodegeneration 28 29929528
2017 Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2. Neurobiology of aging 28 28131462
2023 C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes. Brain : a journal of neurology 27 37100087
2021 TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels. Alzheimer's & dementia : the journal of the Alzheimer's Association 27 33991015
2022 TMEM106B deficiency impairs cerebellar myelination and synaptic integrity with Purkinje cell loss. Acta neuropathologica communications 25 35287730
2021 TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy. Acta neuropathologica 24 34152475
2020 Aged Tmem106b knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non-motor dysfunction. Brain pathology (Zurich, Switzerland) 24 33016371
2011 TMEM106B a novel risk factor for frontotemporal lobar degeneration. Journal of molecular neuroscience : MN 22 21614538
2023 TMEM106B regulates microglial proliferation and survival in response to demyelination. Science advances 20 37146150
2018 Loss of Tmem106b is unable to ameliorate frontotemporal dementia-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity. Acta neuropathologica communications 20 29855382
2021 TMEM106B in humans and Vac7 and Tag1 in yeast are predicted to be lipid transfer proteins. Proteins 17 34347309
2022 TMEM106B Acts as a Modifier of Cognitive and Motor Functions in Amyotrophic Lateral Sclerosis. International journal of molecular sciences 16 36012536
2024 TMEM106B-mediated SARS-CoV-2 infection allows for robust ACE2-independent infection in vitro but not in vivo. Cell reports 15 39480813
2023 Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family. Frontiers in neurology 15 37077569
2021 A novel temporal-predominant neuro-astroglial tauopathy associated with TMEM106B gene polymorphism in FTLD/ALS-TDP. Brain pathology (Zurich, Switzerland) 15 33314436
2024 TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy. Acta neuropathologica 14 38526616
2024 Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice. Acta neuropathologica 13 38526799
2024 Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism. Communications biology 12 39237682
2024 A 3'UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated With Increased Risk for FTLD-TDP. Neurology. Genetics 12 39911968
2021 Loss of Tmem106b leads to cerebellum Purkinje cell death and motor deficits. Brain pathology (Zurich, Switzerland) 12 33709463
2024 Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems. Acta neuropathologica communications 11 38886865
2024 A common Alu insertion in the 3'UTR of TMEM106B is associated with risk of dementia. Alzheimer's & dementia : the journal of the Alzheimer's Association 11 38924247
2023 Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration. Acta neuropathologica communications 11 36707901
2022 Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation. Frontiers in cellular neuroscience 11 36619668
2020 Fronto-temporal dementia risk gene TMEM106B has opposing effects in different lysosomal storage disorders. Brain communications 11 33796852
2017 Association analysis of polymorphisms in VMAT2 and TMEM106B genes for Parkinson's disease, amyotrophic lateral sclerosis and multiple system atrophy. Journal of the neurological sciences 11 28477711
2020 A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay. Brain & development 10 32595021
2023 AAV-GRN partially corrects motor deficits and ALS/FTLD-related pathology in Tmem106bGrn mice. iScience 9 37519899
2025 Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health. Molecular neurodegeneration 7 40269985
2025 The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases. Molecular neurodegeneration 7 40713630
2024 Physiological shedding and C-terminal proteolytic processing of TMEM106B. Cell reports 7 39709600
2024 TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy in transgenic Caenorhabditis elegans. Alzheimer's & dementia : the journal of the Alzheimer's Association 7 39711302
2018 TMEM106B, a risk factor for FTLD and aging, has an intrinsically disordered cytoplasmic domain. PloS one 7 30332472
2017 TMEM106B and ApoE polymorphisms in CHMP2B-mediated frontotemporal dementia (FTD-3). Neurobiology of aging 7 28888721
2015 Association of TMEM106B rs1990622 marker and frontotemporal dementia: evidence for a recessive effect and meta-analysis. Journal of Alzheimer's disease : JAD 7 25096617
2024 Physiological and pathological functions of TMEM106B in neurodegenerative diseases. Cellular and molecular life sciences : CMLS 6 38710967
2024 TMEM106B Knockdown Exhibits a Neuroprotective Effect in Parkinson's Disease via Decreasing Inflammation and Iron Deposition. Molecular neurobiology 6 39044012
2024 Tracing TMEM106B fibril deposition in aging and Parkinson's disease with dementia brains. Life medicine 6 39872397
2023 The identification of high-performing antibodies for transmembrane protein 106B (TMEM106B) for use in Western blot, immunoprecipitation, and immunofluorescence. F1000Research 6 37545650
2023 Antibody-recognizing residues 188-211 of TMEM106B exhibit immunohistochemical reactivity with the TMEM106B C-terminal fragment. Frontiers in neuroscience 6 37937069
2020 Progranulin and TMEM106B: when two become wan. EMBO reports 6 32985120
2025 TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43Q331K knock-in mouse model. Communications biology 5 40011708
2024 Novel Omicron Variants Enhance Anchored Recognition of TMEM106B: A New Pathway for SARS-CoV-2 Cellular Invasion. The journal of physical chemistry letters 5 38206837
2024 Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration. Neurology 5 39321401
2023 TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury. Cells 5 37443768
2023 A 3'UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated with Increased Risk for FTLD-TDP. medRxiv : the preprint server for health sciences 5 37461476
2023 Unveiling TMEM106B: SARS-CoV-2's secret entrance to the cell. Cell 5 37541193
2023 TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models. iScience 5 37965143

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