CoChat
Sign Up
Cited by 2Thyroid Disorders and TreatmentsThyroid Cancer Diagnosis and TreatmentAmino Acid Enzymes and Metabolism

The amino acid transporter Mct10/Tat1 is important to maintain the TSH receptor at its canonical basolateral localization and assures regular turnover of thyroid follicle cells in Male mice

Open access
Venugopalan, Vaishnavi, Al-Hashimi, Alaa, Weber, Jonas, Rehders, Maren, Qatato, Maria, Wirth, Eva K., Schweizer, Ulrich, Heuer, Heike +2 more·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms22115776PMC PMC8198332
Open this paper in CoChat — free accountOpen PDF

Abstract

Cathepsin K-mediated thyroglobulin proteolysis contributes to thyroid hormone (TH) liberation, while TH transporters like Mct8 and Mct10 ensure TH release from thyroid follicles into the blood circulation. Thus, thyroid stimulating hormone (TSH) released upon TH demand binds to TSH receptors of thyrocytes, where it triggers Gαq-mediated short-term effects like cathepsin-mediated thyroglobulin utilization, and Gαs-mediated long-term signaling responses like thyroglobulin biosynthesis and thyrocyte proliferation. As reported recently, mice lacking Mct8 and Mct10 on a cathepsin K-deficient background exhibit excessive thyroglobulin proteolysis hinting towards altered TSH receptor signaling. Indeed, a combination of canonical basolateral and non-canonical vesicular TSH receptor localization was observed in Ctsk−/−/Mct8−/y/Mct10−/− mice, which implies prolonged Gαs-mediated signaling since endo-lysosomal down-regulation of the TSH receptor was not detected. Inspection of single knockout genotypes revealed that the TSH receptor localizes basolaterally in Ctsk−/− and Mct8−/y mice, whereas its localization is restricted to vesicles in Mct10−/− thyrocytes. The additional lack of cathepsin K reverses this effect, because Ctsk−/−/Mct10−/− mice display TSH receptors basolaterally, thereby indicating that cathepsin K and Mct10 contribute to TSH receptor homeostasis by maintaining its canonical localization in thyrocytes. Moreover, Mct10−/− mice displayed reduced numbers of dead thyrocytes, while their thyroid gland morphology was comparable to wild-type controls. In contrast, Mct8−/y, Mct8−/y/Mct10−/−, and Ctsk−/−/Mct8−/y/Mct10−/− mice showed enlarged thyroid follicles and increased cell death, indicating that Mct8 deficiency results in altered thyroid morphology. We conclude that vesicular TSH receptor localization does not result in different thyroid tissue architecture; however, Mct10 deficiency possibly modulates TSH receptor signaling for regulating thyrocyte survival.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/ijms22115776

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MCT10 plays an important role in maintaining TSHR at the basolateral plasma membrane of thyrocytes; in murine models lacking MCT10, TSHR localization is restricted to vesicles.

    “Besides, MCT10 plays an important role in maintaining TSHR at the basolateral plasma membrane of the thyrocytes. In murine models lacking MCT10, the localization of TSHR is restricted to vesicles (197).”

    From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [197]

    Results §2.2 reports that Mct10−/− thyrocytes have TSH receptors exclusively in vesicles, supporting MCT10’s role in maintaining basolateral localization. But the claim is too broad for all murine models lacking MCT10: the same section reports that additional cathepsin K deficiency maintains basolateral TSH receptor localization. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 39

  1. [1]Brix K. Qatato M. Szumska J. Venugopalan V. Rehders M. Thyroglobulin Storage, Processing and Degradation for Thyroid Hormone Liberation The Thyroid and Its Diseases Luster M. Duntas L.H. Wartofsky L. Springer International Publishing New York, NY, USA 2019 25 48 10.1007/978-3-319-72102-6_3 · DOI
  2. [2]Groeneweg S. van Geest F.S. Peeters R.P. Heuer H. Visser W.E. Thyroid Hormone Transporters Endocr. Rev. 2020 41 146 201 10.1210/endrev/bnz008 31754699 · DOI · Paper page
  3. [3]Brix K. Szumska J. Weber J. Qatato M. Venugopalan V. Al-Hashimi A. Rehders M. Auto-Regulation of the Thyroid Gland Beyond Classical Pathways Exp. Clin. Endocrinol. Diabetes Off. J. Ger. Soc. Endocrinol. Ger. Diabetes Assoc. 2020 128 437 445 10.1055/a-1080-2969 32074633 · DOI · Paper page
  4. [4]Fliers E. Kalsbeek A. Boelen A. Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis Eur. J. Endocrinol. 2014 171 R197 R208 10.1530/EJE-14-0285 25005935 · DOI · Paper page
  5. [5]Ortiga-Carvalho T.M. Chiamolera M.I. Pazos-Moura C.C. Wondisford F.E. Hypothalamus-Pituitary-Thyroid Axis Compr. Physiol. 2016 6 1387 1428 10.1002/cphy.c150027 27347897 · DOI
  6. [6]Venugopalan V. Al-Hashimi A. Rehders M. Golchert J. Reinecke V. Homuth G. Völker U. Manirajah M. Touzani A. Weber J. The Thyroid Hormone Transporter Mct8 Restricts Cathepsin-Mediated Thyroglobulin Processing in Male Mice through Thyroid Auto-Regulatory Mechanisms That Encompass Autophagy Int. J. Mol. Sci. 2021 22 462 10.3390/ijms22010462 PMC7796480 33466458 · DOI
  7. [7]Qatato M. Szumska J. Skripnik V. Rijntjes E. Köhrle J. Brix K. Canonical TSH Regulation of Cathepsin-Mediated Thyroglobulin Processing in the Thyroid Gland of Male Mice Requires Taar1 Expression Front. Pharmacol. 2018 9 221 10.3389/fphar.2018.00221 29615904 PMC5870035 · DOI
  8. [8]Weber J. McInnes J. Kizilirmak C. Rehders M. Qatato M. Wirth E.K. Schweizer U. Verrey F. Heuer H. Brix K. Interdependence of thyroglobulin processing and thyroid hormone export in the mouse thyroid gland Eur. J. Cell Biol. 2017 96 440 456 10.1016/j.ejcb.2017.02.002 28274595 · DOI · Paper page
  9. [9]Führer D. Brix K. Biebermann H. Understanding the Healthy Thyroid State in 2015 Eur. Thyroid J. 2015 4 1 8 10.1159/000431318 PMC4640297 26601068 · DOI
  10. [10]Wirth E.K. Sheu S.Y. Chiu-Ugalde J. Sapin R. Klein M.O. Mossbrugger I. Quintanilla-Martinez L. de Angelis M.H. Krude H. Riebel T. Monocarboxylate transporter 8 deficiency: Altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy Eur. J. Endocrinol. 2011 165 555 561 10.1530/EJE-11-0369 21813593 · DOI
  11. [11]Müller J. Mayerl S. Visser T.J. Darras V.M. Boelen A. Frappart L. Mariotta L. Verrey F. Heuer H. Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency Endocrinology 2014 155 315 325 10.1210/en.2013-1800 24248460 · DOI · Paper page
  12. [12]Kero J. Ahmed K. Wettschureck N. Tunaru S. Wintermantel T. Greiner E. Schütz G. Offermanns S. Thyrocyte-specific Gq/G11 deficiency impairs thyroid function and prevents goiter development J. Clin. Investig. 2007 117 2399 2407 10.1172/JCI30380 17694176 PMC1937498 · DOI · Paper page
  13. [13]Friedrichs B. Tepel C. Reinheckel T. Deussing J. von Figura K. Herzog V. Peters C. Saftig P. Brix K. Thyroid functions of mouse cathepsins B, K, and L J. Clin. Investig. 2003 111 1733 1745 10.1172/JCI15990 12782676 PMC156100 · DOI · Paper page
  14. [14]Dauth S. Rakov H. Sîrbulescu R.F. Ilieş I. Weber J. Batbajar Dugershaw B. Braun D. Rehders M. Wirth E.K. Führer D. Function of Cathepsin K in the Central Nervous System of Male Mice is Independent of Its Role in the Thyroid Gland Cell. Mol. Neurobiol. 2020 40 695 710 10.1007/s10571-019-00765-6 31808010 PMC11448817 · DOI
  15. [16]Müller J. Heuer H. Understanding the hypothalamus-pituitary-thyroid axis in mct8 deficiency Eur. Thyroid J. 2012 1 72 79 10.1159/000339474 24783000 PMC3821472 · DOI
  16. [17]Calebiro D. Nikolaev V.O. Gagliani M.C. de Filippis T. Dees C. Tacchetti C. Persani L. Lohse M.J. Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors PLoS Biol. 2009 7 e1000172 10.1371/journal.pbio.1000172 19688034 PMC2718703 · DOI
  17. [18]Calebiro D. Nikolaev V.O. Persani L. Lohse M.J. Signaling by internalized G-protein-coupled receptors Trends Pharm. Sci 2010 31 221 228 10.1016/j.tips.2010.02.002 20303186 · DOI
  18. [19]Godbole A. Lyga S. Lohse M.J. Calebiro D. Internalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription Nat. Commun. 2017 8 443 10.1038/s41467-017-00357-2 28874659 PMC5585343 · DOI
  19. [20]Latif R. Graves P. Davies T.F. Oligomerization of the human thyrotropin receptor: Fluorescent protein-tagged hTSHR reveals post-translational complexes J. Biol. Chem. 2001 276 45217 45224 10.1074/jbc.M103727200 11535591 · DOI
  20. [21]Davies T. Marians R. Latif R. The TSH receptor reveals itself J. Clin. Investig. 2002 110 161 164 10.1172/JCI0216234 12122107 PMC151075 · DOI
  21. [22]Fischer J. Kleinau G. Rutz C. Zwanziger D. Khajavi N. Muller A. Rehders M. Brix K. Worth C.L. Fuhrer D. Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level Cell. Mol. Life Sci. 2018 75 2227 2239 10.1007/s00018-017-2728-1 29290039 PMC11105501 · DOI · Paper page
  22. [23]Brix K. Lemansky P. Herzog V. Evidence for extracellularly acting cathepsins mediating thyroid hormone liberation in thyroid epithelial cells Endocrinology 1996 137 1963 1974 10.1210/endo.137.5.8612537 8612537 · DOI
  23. [24]Linke M. Jordans S. Mach L. Herzog V. Brix K. Thyroid stimulating hormone upregulates secretion of cathepsin B from thyroid epithelial cells Biol. Chem. 2002 383 773 784 10.1515/BC.2002.081 12108542 · DOI · Paper page
  24. [25]Dumont J.E. Lamy F. Roger P. Maenhaut C. Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors Physiol. Rev. 1992 72 667 697 10.1152/physrev.1992.72.3.667 1320763 · DOI
  25. [26]Nilsson M. Fagman H. Development of the thyroid gland Development (Camb. Engl.) 2017 144 2123 2140 10.1242/dev.145615 28634271 · DOI
  26. [28]Allgeier A. Offermanns S. Van Sande J. Spicher K. Schultz G. Dumont J.E. The human thyrotropin receptor activates G-proteins Gs and Gq/11 J. Biol. Chem. 1994 269 13733 13735 10.1016/S0021-9258(17)36705-4 8188646 · DOI · Paper page
  27. [29]Allen M.D. Neumann S. Gershengorn M.C. Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2011 25 3687 3694 10.1096/fj.11-188961 PMC3177577 21705666 · DOI · Paper page
  28. [30]Botta R. Lisi S. Pinchera A. Giorgi F. Marcocci C. Taddei A.R. Fausto A.M. Bernardini N. Ippolito C. Mattii L. Sortilin is a putative postendocytic receptor of thyroglobulin Endocrinology 2009 150 509 518 10.1210/en.2008-0953 18687776 · DOI · Paper page
  29. [31]Giordano C. Richiusa P. Bagnasco M. Salmaso C. Pizzolanti G. Galluzzo A. Thyrocytes—Not innocent bystanders in autoimmune disease Nat. Immunol. 2001 2 183 10.1038/85224 11224508 · DOI
  30. [32]Lin J.D. The role of apoptosis in autoimmune thyroid disorders and thyroid cancer BMJ 2001 322 1525 1527 10.1136/bmj.322.7301.1525 11420275 PMC1120572 · DOI
  31. [33]Stassi G. De Maria R. Autoimmune thyroid disease: New models of cell death in autoimmunity Nat. Rev. Immunol. 2002 2 195 204 10.1038/nri750 11913070 · DOI
  32. [34]Palazzo F.F. Hammond L.J. Goode A.W. Mirakian R. Death of the autoimmune thyrocyte: Is it pushed or does it jump? Thyroid Off. J. Am. Thyroid Assoc. 2000 10 561 572 10.1089/thy.2000.10.561 10958308 · DOI
  33. [35]Andrikoula M. Tsatsoulis A. The role of Fas-mediated apoptosis in thyroid disease Eur. J. Endocrinol. 2001 144 561 568 10.1530/eje.0.1440561 11375789 · DOI
  34. [36]Tsatsoulis A. The role of apoptosis in thyroid disease Minerva Med. 2002 93 169 180 12094148
  35. [37]McQuin C. Goodman A. Chernyshev V. Kamentsky L. Cimini B.A. Karhohs K.W. Doan M. Ding L. Rafelski S.M. Thirstrup D. CellProfiler 3.0: Next-generation image processing for biology PLoS Biol. 2018 16 e2005970 10.1371/journal.pbio.2005970 29969450 PMC6029841 · DOI
  36. [38]Neuhoff V. Philipp K. Zimmer H.G. Mesecke S. A simple, versatile, sensitive and volume-independent method for quantitative protein determination which is independent of other external influences Hoppe-Seyler’s Z. Physiol. Chem. 1979 360 1657 1670 10.1515/bchm2.1979.360.2.1657 92445 · DOI
  37. [39]Abdulrahman R.M. Boon M.R. Sips H.C. Guigas B. Rensen P.C. Smit J.W. Hovens G.C. Impact of Metformin and compound C on NIS expression and iodine uptake in vitro and in vivo: A role for CRE in AMPK modulation of thyroid function Thyroid Off. J. Am. Thyroid Assoc. 2014 24 78 87 10.1089/thy.2013.0041 23819433 · DOI
  38. [40]Lu X.-Y. Shi X.-J. Hu A. Wang J.-Q. Ding Y. Jiang W. Sun M. Zhao X. Luo J. Qi W. Feeding induces cholesterol biosynthesis via the mTORC1–USP20–HMGCR axis Nature 2020 588 479 484 10.1038/s41586-020-2928-y 33177714 · DOI
  39. [41]Kunath A. Weiner J. Krause K. Rehders M. Pejkovska A. Gericke M. Biniossek M.L. Dommel S. Kern M. Ribas-Latre A. Role of Kallikrein 7 in Body Weight and Fat Mass Regulation Biomedicines 2021 9 131 10.3390/biomedicines9020131 33572949 PMC7912635 · DOI

Cited by

Sorted by citations

Authors
Venugopalan, V., Al-Hashimi, A., Weber, J., Rehders, M., Qatato, M., Wirth, E. K., Schweizer, U., Heuer, H., Verrey, F., & Brix, K.
Affiliations
  • Constructor University (DE)
  • Humboldt-Universität zu Berlin (DE)
  • University Hospital Bonn (DE)
  • Essen University Hospital (DE)
  • University of Zurich (CH)
Corresponding author
Brix, Klaudia
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-05-28
Volume
22
Issue
11
Pages
5776
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms22115776
PMC
PMC8198332
OpenAlex
W3165493387
Cited by
2
References
2
Citations by year
2022: 2
FWCI
0.37
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Deutsche Forschungsgemeinschaft (BR 1308/11-1, 11-2, SCHW 914/6-1, HE 3418/7-1, 7-2)
  • Charité – Universitätsmedizin Berlin (Rahel-Hirsch stipend to E.K.W.)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31_166430/1 to F.V.)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
MCT10, TAT1, MCT8, TSH receptor, thyroid follicular cells, cathepsin K, thyroid hormone secretion, Gαs signaling, Gαq signaling, thyroid morphology, thyroid hormone transporters
MeSH terms
Thyroid Epithelial Cells, Animals, Male, Mice, Inbred C57BL, Receptors, Thyrotropin, Thyroglobulin, Thyroid Gland, Thyroid Hormones, Thyrotropin, Mice, Knockout, Microscopy, Confocal, Fluorescent Antibody Technique, Indirect, Amino Acid Transport Systems, Neutral, Mice, Cathepsin K

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review