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Cited by 6Vector-borne infectious diseasesInsect symbiosis and bacterial influencesEndoplasmic Reticulum Stress and Disease

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ATF6 enables pathogen infection in ticks by inducing stomatin and altering cholesterol dynamics

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Vosbigian, Kaylee A., Wright, Sarah J., Steiert, Brianna P., Rosche, Kristin L., Fisk, Elis A., Ramirez-Zepp, Elisabeth, Park, Jason M., Shelden, Eric A., Shaw, Dana K.·2025·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2501045122PMC PMC12207416

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Abstract

How tick-borne pathogens interact with their hosts has been primarily studied in vertebrates where disease is observed. Comparatively less is known about pathogen interactions within the tick. Here, we report that Ixodes scapularis ticks infected with either Anaplasma phagocytophilum (causative agent of anaplasmosis) or Borrelia burgdorferi (causative agent of Lyme disease) show activation of the ATF6 branch of the unfolded protein response (UPR). Disabling ATF6 functionally restricts pathogen survival in ticks. When stimulated, ATF6 functions as a transcription factor, but is the least understood out of the three UPR pathways. To interrogate the Ixodes ATF6 transcriptional network, we developed a custom R script to query tick promoter sequences. This revealed stomatin as a potential gene target, which has roles in lipid homeostasis and vesical transport. Ixodes stomatin was experimentally validated as a bona fide ATF6-regulated gene through luciferase reporter assays, pharmacological activators, RNA interference transcriptional repression, and immunofluorescence microscopy. Silencing stomatin decreased A. phagocytophilum colonization in Ixodes and disrupted cholesterol dynamics in tick cells. Furthermore, blocking stomatin restricted cholesterol availability to the bacterium, thereby inhibiting growth and survival. Taken together, we have identified the Ixodes ATF6 pathway as a contributor to vector competence through Stomatin-regulated cholesterol homeostasis. Moreover, our custom, web-based transcription factor binding site search tool “ArthroQuest” revealed that the ATF6-regulated nature of stomatin is unique to blood-feeding arthropods. Collectively, these findings highlight the importance of studying fundamental processes in nonmodel organisms.

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Fig. 1. ATF6 is induced by tick-borne pathogens during infection and supports vector colonization. (A) Schematic depicting ATF6 activation. (B) HEK 293T cells were transfected with an ATF6 luciferase reporter plasmid. Transfected cells were infected with A. phagocytophilum (MOI 50) or B. burgdorferi (MOI 200) for 18 h and normalized to no infection (−). RLU is relative luminescence units. (C and D) Gene expression of atf6 in I. scapularis larvae rested for 7 d after feeding on Anaplasma-infected mice (C) and rested for 14 d after feeding on Borrelia-infected mice (D). Expression was assessed via qRT-PCR. Each data point is representative of 1 larva. (−) is no infection. A.p. is A. phagocytophilum. B.b. is B. burgdorferi. (E) ATF6 (55 kDa) immunoblot against nuclear extracts of ISE6 tick cells that were either uninfected (−) or persistently infected with A. phagocytophilum (A.p.). Histone H3 was probed as a loading control (16 kDa). (F) RNAi knockdown of atf6 in ISE6 cells for 5 d and infected with A. phagocytophilum (MOI 50). scRNA, scrambled RNA; siRNA, small interfering RNA. Experiments are representative of at least two experimental replicates. *P < 0.05.
Fig. 1. ATF6 is induced by tick-borne pathogens during infection and supports vector colonization. (A) Schematic depicting ATF6 activation. (B) HEK 293T cells were transfected with an ATF6 luciferase reporter plasmid. Transfected cells were infected with A. phagocytophilum (MOI 50) or B. burgdorferi (MOI 200) for 18 h and normalized to no infection (−). RLU is relative luminescence units. (C and D) Gene expression of atf6 in I. scapularis larvae rested for 7 d after feeding on Anaplasma-infected mice (C) and rested for 14 d after feeding on Borrelia-infected mice (D). Expression was assessed via qRT-PCR. Each data point is representative of 1 larva. (−) is no infection. A.p. is A. phagocytophilum. B.b. is B. burgdorferi. (E) ATF6 (55 kDa) immunoblot against nuclear extracts of ISE6 tick cells that were either uninfected (−) or persistently infected with A. phagocytophilum (A.p.). Histone H3 was probed as a loading control (16 kDa). (F) RNAi knockdown of atf6 in ISE6 cells for 5 d and infected with A. phagocytophilum (MOI 50). scRNA, scrambled RNA; siRNA, small interfering RNA. Experiments are representative of at least two experimental replicates. *P < 0.05.CC BY-NC-ND · PubMed Central
Fig. 2. Predicting the ATF6 regulatory network in ticks. (A) The I. scapularis ATF6 (orange) predicted with AlphaFold has a conserved DNA binding domain compared to the human ortholog (green). (B) A portion of the bZIP domain and the DNA binding residues on ATF6 are visualized. (C) Schematic of the developed R script. (D) Comparison of genes predicted to be regulated by ATF6 from I. scapularis, D. melanogaster, and Homo sapiens. (E) GO terms and Reactome pathways represented in predicted ATF6-regulated genes from the I. scapularis genome.
Fig. 2. Predicting the ATF6 regulatory network in ticks. (A) The I. scapularis ATF6 (orange) predicted with AlphaFold has a conserved DNA binding domain compared to the human ortholog (green). (B) A portion of the bZIP domain and the DNA binding residues on ATF6 are visualized. (C) Schematic of the developed R script. (D) Comparison of genes predicted to be regulated by ATF6 from I. scapularis, D. melanogaster, and Homo sapiens. (E) GO terms and Reactome pathways represented in predicted ATF6-regulated genes from the I. scapularis genome.CC BY-NC-ND · PubMed Central
Fig. 3. ATF6 upregulates stomatin during infection in ticks which supports Anaplasma. (A) The AlphaFold3 predicted DNA–protein complex with I. scapularis nATF6 (tan) and the predicted promoter of stomatin (teal). The ATF6 binding site is highlighted in yellow and DNA binding residues highlighted in purple. (B and C) stomatin expression quantified from (B) ISE6 cells treated with 5 µM to 50 µM of AA147 for 24 h and (C) ISE6 cells transfected with siRNA targeting atf6 or a scrambled control. (D) HEK 293T cells were cotransfected with plasmids constitutively expressing I. scapularis nATF6, I. scapularis NF-Y, and a luciferase reporter plasmid with the stomatin promoter. Luciferase activity was normalized to the control containing only the luciferase reporter plasmid. RLU is relative luminescence units. (E and F) Gene expression of larvae rested for 7 d after being fed on Anaplasma-infected mice (E) or rested for 14 d after being fed on B. burgdorferi–infected mice (F). (G) stomatin gene expression from unfed, infected I. scapularis nymphs. A.p. is A. phagocytophilum. B.b. is B. burgdorferi. Expression assessed via qRT-PCR. (H) ISE6 cells were transfected with siRNA or a scrambled control. Cells were infected with A. phagocytophilum (MOI 50) for 18 h. (I) siRNA-treated or scrambled control-treated larvae were fed on A. phagocytophilum–infected mice. Each data point is representative of 1 larva. Open and closed dots represent experimental replicates 1 and 2. Gene silencing and bacterial burden were measured by qRT-PCR. scRNA, scrambled RNA; siRNA, small interfering RNA; *P < 0.05.
Fig. 3. ATF6 upregulates stomatin during infection in ticks which supports Anaplasma. (A) The AlphaFold3 predicted DNA–protein complex with I. scapularis nATF6 (tan) and the predicted promoter of stomatin (teal). The ATF6 binding site is highlighted in yellow and DNA binding residues highlighted in purple. (B and C) stomatin expression quantified from (B) ISE6 cells treated with 5 µM to 50 µM of AA147 for 24 h and (C) ISE6 cells transfected with siRNA targeting atf6 or a scrambled control. (D) HEK 293T cells were cotransfected with plasmids constitutively expressing I. scapularis nATF6, I. scapularis NF-Y, and a luciferase reporter plasmid with the stomatin promoter. Luciferase activity was normalized to the control containing only the luciferase reporter plasmid. RLU is relative luminescence units. (E and F) Gene expression of larvae rested for 7 d after being fed on Anaplasma-infected mice (E) or rested for 14 d after being fed on B. burgdorferi–infected mice (F). (G) stomatin gene expression from unfed, infected I. scapularis nymphs. A.p. is A. phagocytophilum. B.b. is B. burgdorferi. Expression assessed via qRT-PCR. (H) ISE6 cells were transfected with siRNA or a scrambled control. Cells were infected with A. phagocytophilum (MOI 50) for 18 h. (I) siRNA-treated or scrambled control-treated larvae were fed on A. phagocytophilum–infected mice. Each data point is representative of 1 larva. Open and closed dots represent experimental replicates 1 and 2. Gene silencing and bacterial burden were measured by qRT-PCR. scRNA, scrambled RNA; siRNA, small interfering RNA; *P < 0.05.CC BY-NC-ND · PubMed Central
Fig. 4. Stomatin supports infection by facilitating A. phagocytophilum cholesterol uptake. (A) Total cholesterol quantified from A. phagocytophilum–infected ISE6 cells compared to uninfected cells (−). Each point represents an experimental replicate. (B) Cholesterol quantified from cells treated with silencing RNAs targeting stomatin or scrambled controls. Gene silencing was measured by qRT-PCR. (C) Representative images of ISE6 cells transfected with silencing RNAs targeting stomatin or a scrambled control. Cells were fixed and stained with filipin. Scale bar is 10 microns. (D) Relative fluorescence intensity of filipin staining between stomatin-silenced cells or scrambled controls. Each dot represents one analyzed image. (E) Representative images of A. phagocytophilum infected ISE6 cells transfected for 5 d with silencing RNAs targeting stomatin or a scrambled control. Cells were stained with filipin (blue) and an antibody targeting A. phagocytophilum VirD4 (red). White dotted lines outline morulae. Scale bar is 10 microns. (F) Relative fluorescence intensity of filipin staining in the morulae between stomatin-silenced cells or scrambled controls. Each dot represents one cell analyzed. (G) Morulae size measurements in stomatin-silenced cells or scrambled controls. Each dot represents one morula measured. (H) Cholesterol quantified from A. phagocytophilum grown in stomatin-depleted ISE6 tick cells. scRNA, scrambled RNA; siRNA, small interfering RNA. scStomatin, scrambled controls. siStomatin, siRNA targeting stomatin. A.U., arbitrary units. Experiments are representative of at least two experimental replicates. *P < 0.05.
Fig. 4. Stomatin supports infection by facilitating A. phagocytophilum cholesterol uptake. (A) Total cholesterol quantified from A. phagocytophilum–infected ISE6 cells compared to uninfected cells (−). Each point represents an experimental replicate. (B) Cholesterol quantified from cells treated with silencing RNAs targeting stomatin or scrambled controls. Gene silencing was measured by qRT-PCR. (C) Representative images of ISE6 cells transfected with silencing RNAs targeting stomatin or a scrambled control. Cells were fixed and stained with filipin. Scale bar is 10 microns. (D) Relative fluorescence intensity of filipin staining between stomatin-silenced cells or scrambled controls. Each dot represents one analyzed image. (E) Representative images of A. phagocytophilum infected ISE6 cells transfected for 5 d with silencing RNAs targeting stomatin or a scrambled control. Cells were stained with filipin (blue) and an antibody targeting A. phagocytophilum VirD4 (red). White dotted lines outline morulae. Scale bar is 10 microns. (F) Relative fluorescence intensity of filipin staining in the morulae between stomatin-silenced cells or scrambled controls. Each dot represents one cell analyzed. (G) Morulae size measurements in stomatin-silenced cells or scrambled controls. Each dot represents one morula measured. (H) Cholesterol quantified from A. phagocytophilum grown in stomatin-depleted ISE6 tick cells. scRNA, scrambled RNA; siRNA, small interfering RNA. scStomatin, scrambled controls. siStomatin, siRNA targeting stomatin. A.U., arbitrary units. Experiments are representative of at least two experimental replicates. *P < 0.05.CC BY-NC-ND · PubMed Central
Fig. 5. ATF6 supports arthropod infection through Stomatin-regulated cholesterol delivery to the pathogen. (A) Infection activates ATF6 which translocates to the nucleus and upregulates stomatin expression. Stomatin regulates cholesterol distribution in the cell and to the Anaplasma containing vacuole for growth and survival in ticks. (B) ArthroQuest was used to identify organisms containing ATF6 binding sites in the promoter regions of Stomatin orthologs. Stomatin orthologs were identified using the Ixodes protein sequence. Green checkmarks indicate that the top ortholog contains an ATF6 binding site in the promoter region. Yellow checkmarks indicate that a significant ortholog hit contains an ATF6 binding site in the promoter region. Red “X” indicates all BLAST hits lack an ATF6 binding site.
Fig. 5. ATF6 supports arthropod infection through Stomatin-regulated cholesterol delivery to the pathogen. (A) Infection activates ATF6 which translocates to the nucleus and upregulates stomatin expression. Stomatin regulates cholesterol distribution in the cell and to the Anaplasma containing vacuole for growth and survival in ticks. (B) ArthroQuest was used to identify organisms containing ATF6 binding sites in the promoter regions of Stomatin orthologs. Stomatin orthologs were identified using the Ixodes protein sequence. Green checkmarks indicate that the top ortholog contains an ATF6 binding site in the promoter region. Yellow checkmarks indicate that a significant ortholog hit contains an ATF6 binding site in the promoter region. Red “X” indicates all BLAST hits lack an ATF6 binding site.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Vosbigian, K. A., Wright, S. J., Steiert, B. P., Rosche, K. L., Fisk, E. A., Ramirez-Zepp, E., Park, J. M., Shelden, E. A., & Shaw, D. K.
Affiliations
Washington State University (US)
Corresponding author
Shaw, Dana K.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2025-06-17
Volume
122
Issue
25
Pages
e2501045122-e2501045122
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2501045122
PMC
PMC12207416
OpenAlex
W4411360127
Cited by
6
References
2
Citations by year
2026: 4 · 2025: 2
FWCI
5.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI162819, R21AI139772, R21AI148578, T32GM008336, T32AI007025)
  • HHS | NIH | National Institute of Biomedical Imaging and Bioengineering (R25EB027606)
  • Achievement Rewards for College Scientists Foundation (ARCS)
Topics
  • Life Sciences › Immunology and Microbiology › Parasitology › Vector-borne infectious diseases
  • Life Sciences › Agricultural and Biological Sciences › Insect Science › Insect symbiosis and bacterial influences
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
ATF6, unfolded protein response, Ixodes scapularis, stomatin, cholesterol homeostasis, Anaplasma phagocytophilum, Borrelia burgdorferi, tick-borne pathogens, tick vector competence, tick-borne diseases, transcription factor binding site prediction, lipid homeostasis

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Vosbigian, K. A., Wright, S. J., Steiert, B. P., Rosche, K. L., Fisk, E. A., Ramirez-Zepp, E., Park, J. M., Shelden, E. A., & Shaw, D. K. (2025). ATF6 enables pathogen infection in ticks by inducing stomatin and altering cholesterol dynamics. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2501045122