As the COVID-19 pandemic appears to be weakening its grip on the world, scientists are learning more about what makes the new coronavirus tick. Three different research groups independently discovered, to their surprise, that SARS-CoV-2 infects human cells only if the cells express the lysosomal receptor TMEM106B. Its gene is a known factor in dementia, but whether the dementia risk variants affect Covid-19 remain to be seen.

The researchers used genome-wide CRISPR knockout screens to assess which genes are required for Sars-CoV-2 to be able to infect human liver cell lines. They exposed cell libraries to SARS-CoV-2, and looked for knockout cells that failed to churn out virus as an indication that the missing gene is important to establish a full cycle of infection. The three groups converged on the same lysosomal receptor, TMEM106B, a genetic risk factor for frontotemporal dementia and Alzheimer’s disease (Sep 2020 news; Mar 2020 news; Feb 2021 newsJun 2020 news). 

Researchers led by Dirk Daelemans, KU Leuven, Belgium, reported their findings in the March 8 Nature Genetics. The other two papers had appeared back-to-back in the January 7 Cell. Andreas Puschnik, Chan Zuckerberg Biohub, and Melanie Ott, Gladstone Institutes, both in San Francisco, were senior authors on one. The other came from the labs of John Poirier, NYU Grossman School of Medicine, and Charles Rice, Rockefeller University, both in New York.

Exactly what makes TMEM106B essential for SARS-CoV-2 infection remains a mystery, but Markus Damme, University of Kiel, Germany, noted that related coronaviruses hitch a ride on lysosomes to get out of the cell. “Future work is needed to determine if SARS-CoV-2 is hijacking TMEM106B for binding in lysosomes after being released from ACE2 upon endocytosis,” Damme wrote to Alzforum (full comment below).

Whether carriers of TMEM106B risk variants are more or less likely to get COVID-19 is unclear. “Major differences in disease severity in COVID-19 are well-known, and it might be interesting to figure out if there is any direct correlation between the SNPs and disease severity. It might also be interesting to see if FTD patients are more prone to a severe course of the disease,” wrote Damme.—Chelsea Weidman Burke


  1. Variants in TMEM106B, coding for a lysosomal transmembrane protein, were recognized as important genetic modifiers in different neurodegenerative diseases and, in particular, in FTD patients harboring GRN mutations.

    Now, TMEM106B comes into the spotlight for a disease that has changed our lives for more than one year: COVID-19. With outstanding reproducibility, three elegant, independent studies identified TMEM106B in unbiased genome-wide CRISPR knockout screens as a crucial host factor for SARS-CoV-2 infection: Cells lacking TMEM106B can hardly be infected with the nasty virus.

    A critical question, now, is what makes TMEM106B so essential for the virus. Many viruses bind to the extracellular domain of plasma-membrane-bound receptors and bind a second intracellular receptor upon endocytosis. Examples include the lysosomal membrane protein LAMP1 for the Lassa virus, NPC1 for the Ebola virus, or Scarb2 for Enterovirus 71. Future work is needed to determine if SARS-CoV-2 is hijacking TMEM106B for binding in lysosomes after being released from ACE2 upon endocytosis. In this regard, it should be mentioned that β-coronaviruses utilize lysosomal trafficking for egress rather than the biosynthetic secretory pathway more commonly used by other enveloped viruses (Ghosh et al., 2020). 

    Other scenarios are also feasible: Other hits identified in the screens include genes that play essential functions in autophagy (TMEM41B, CCZ1B) and lysosomal (VAC14) acidification, processes in which TMEM106B was also previously shown to be involved (Werner et al., 2020; Lüningschrör et al., 2020; Klein et al., 2017). These questions will be of major importance for future work and possibly developing TMEM106B-targeted therapies for COVID-19, e.g., by using monoclonal antibodies.

    The interesting question is if genetic variants/SNPs in TMEM106B influence infectivity, e.g., in patients harboring the protective coding SNP in the luminal domain that likely gets in direct contact with the virus. Major differences in disease severity in COVID-19 are well known, and it might be interesting to figure out if there is any direct correlation between the SNPs and disease severity. It might also be interesting to see if FTD-patients are more prone to a severe course of COVID-19.


    . β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway. Cell. 2020 Dec 10;183(6):1520-1535.e14. Epub 2020 Oct 27 PubMed.

    . Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice. EMBO Rep. 2020 Oct 5;21(10):e50241. Epub 2020 Sep 14 PubMed.

    . The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons. Cell Rep. 2020 Mar 10;30(10):3506-3519.e6. PubMed.

    . Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. Neuron. 2017 Jul 19;95(2):281-296.e6. PubMed.

  2. TMEM106B first came under the scientific spotlight as a risk gene for frontotemporal lobar degeneration-TDP-43 (FTLD-TDP) (Van Deerlin et al., 2010), but the gene’s clinical implication goes beyond TDP-43 proteinopathy.

    A common TMEM106B haplotype tagged by a missense coding variant, rs3173615C (TMEM106B p.S185T), increases risk of FTLD-TDP (Pottier et al., 2018; Van Deerlin et al., 2010) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) (Yu et al., 2015). Moreover, this locus predicts cognitive impairment in other neurodegenerative disorders, such as amyotrophic lateral sclerosis (Vass et al., 2011) and Parkinson’s disease (Tropea et al., 2019), and is associated with poor cognitive resilience to neuropathology in older adults (White et al., 2017; Yang et al., 2020). Further, the same haplotype has a pleiotropic effect on other diseases and clinical traits, such as major depressive disorder (Wray et al., 2018) and higher triglyceride level (Klarin et al., 2018). Finally, a rare dominant missense mutation in TMEM106B (TMEM106B p.D252N) causes hypomyelinating leukodystrophy, an early onset disorder distinct from TDP-43 proteinopathies (Simons et al., 2017). 

    The three studies discussed here demonstrate that TMEM106B is an essential host protein for SARS-CoV2 infection, expanding the ever-growing list of TMEM106’s pleiotropic roles in human health and diseases. Baggen et al. found that TMEM106B knockout prevented SARS-CoV2 infection, which would be consistent with TMEM106B’s role in viral entry. In addition, COVID-19 patient-derived respiratory epithelial cells (from bronchoalveolar lavage) showed increased TMEM106B expression. These are intriguing observations that might hint at a shared pathophysiology between TDP-43 proteinopathy and viral infection, given accumulating evidence supporting that the TMEM106B FTLD-TDP risk haplotype leads to enhanced TMEM106B function, lysosomal dysfunction, and increased abnormal TDP-43 protein accumulation (e.g., Yang et al., 2020). 

    Nonetheless, it is important to note that we cannot make any direct clinical connections between COVID-19 and TDP-43 proteinopathy from this study, given the clear differences in disease pathophysiology, target organs, and experimental approaches. For example, this study does not tell us whether FTD patients or TMEM106B TDP-43 risk allele carriers would be more susceptible to SARS-CoV2 infection or severe COVID-19.

    Rather, a key message from this study to our field is that TMEM106B is a pleiotropic gene that has versatile physiologic roles in multiple biological processes, which raises a concern that systemic perturbation of TMEM106B to treat TDP-43 proteinopathy could lead to various off-target effects. Therefore, to target TMEM106B in TDP-43 proteinopathy clinical trials, it is critical to further understand the gene’s normal physiological function in various tissues beyond brain.


    . Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat Genet. 2018 Nov;50(11):1514-1523. Epub 2018 Oct 1 PubMed.

    . Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol. 2018 Jun;17(6):548-558. Epub 2018 Apr 30 PubMed.

    . A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain. 2017 Dec 1;140(12):3105-3111. PubMed.

    . TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia. Ann Neurol. 2019 Jun;85(6):801-811. PubMed.

    . Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010 Mar;42(3):234-9. PubMed.

    . Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta Neuropathol. 2011 Mar;121(3):373-80. PubMed.

    . Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data. PLoS Med. 2017 Apr;14(4):e1002287. Epub 2017 Apr 25 PubMed.

    . Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018 May;50(5):668-681. Epub 2018 Apr 26 PubMed.

    . Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology. Neuron. 2020 Aug 5;107(3):496-508.e6. Epub 2020 Jun 10 PubMed.

    . The TMEM106B locus and TDP-43 pathology in older persons without FTLD. Neurology. 2015 Mar 3;84(9):927-34. Epub 2015 Feb 4 PubMed.

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News Citations

  1. Nixing TMEM106b Fans the Flames of Progranulin Deficiency
  2. Without TMEM106B, Lysosomal Traffic Jams Wreak Havoc in Neurons
  3. Massive GWAS Meta-Analysis Digs Up Trove of Alzheimer’s Genes
  4. TMEM106B Variants Regulate Gene Modules, TDP-43 Pathology

Further Reading

Primary Papers

  1. . Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2. Nat Genet. 2021 Mar 8; PubMed.
  2. . Genome-Scale Identification of SARS-CoV-2 and Pan-coronavirus Host Factor Networks. Cell. 2021 Jan 7;184(1):120-132.e14. Epub 2020 Dec 9 PubMed.
  3. . Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses. Cell. 2021 Jan 7;184(1):106-119.e14. Epub 2020 Dec 9 PubMed.