Thyroid functions of mouse cathepsins B, K, and L

Friedrichs, B; Tepel, Carmen; Reinheckel, Thomas; Deussing, Jan M.; Figura, Kurt Von; Herzog, Volker; Peters, Christoph; Säftig, Paul; Brix, Klaudia

doi:10.1172/jci15990

Cited by 194 publications

(145 citation statements)

References 43 publications

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“…Iodinated thyroglobulin (here called TG-T4) can either be stored in the lumen of thyroid follicles or is mobilized by the follicle cells. Mobilization involves solubilization and proteolytic cleavage of TG-T4 by proteases, including cathepsin b (Brix et al, 1996;Friedrichs et al, 2003). The resulting T4 is released into the blood stream as thyroid hormone ( Fig.…”

Section: Expression Of Differentiation Markers Reveals Growth Of the mentioning

confidence: 99%

Analysis of origin and growth of the thyroid gland in zebrafish

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Feitosa

et al. 2006

Developmental Dynamics

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The zebrafish thyroid gland shows a unique pattern of growth as a differentiated endocrine gland. Here, we analyze the onset of differentiation, the contribution of lineages, and the mode of growth of this gland. The expression of genes involved in hormone production and the establishment of epithelial polarity show that differentiation into a first thyroid follicle takes place early during embryonic development. Thyroid follicular tissue then grows along the pharyngeal midline, initially independently of thyroid stimulating hormone. Lineage analysis reveals that thyroid follicle cells are exclusively recruited from the pharyngeal endoderm. The ultimobranchial bodies that merge with the thyroid in mammals form separate glands in zebrafish as visualized by calcitonin precursor gene expression. Mosaic analysis suggests that the first thyroid follicle differentiating at 55 hours postfertilization corresponds later to the most anterior follicle and that new follicles are added caudally.

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Section: Expression Of Differentiation Markers Reveals Growth Of the mentioning

confidence: 99%

Analysis of origin and growth of the thyroid gland in zebrafish

Alt

Reibe

Feitosa

et al. 2006

Developmental Dynamics

153

141

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“…Studies using cathepsin L (Ctsl)-gene-deficient mice 1 revealed an important role of Ctsl in cardiac homeostasis (4 -6) and a contribution of Ctsl to MHC II-mediated antigen presentation (7,8) and prohormone processing (9,10). In a mouse model of pancreatic neuroendocrine cancer, Ctsl promoted tumor growth and invasiveness (11,12).…”

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confidence: 99%

Deletion of Cysteine Cathepsins B or L Yields Differential Impacts on Murine Skin Proteome and Degradome

Tholen

Biniossek

Gansz

et al. 2013

Molecular & Cellular Proteomics

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Numerous studies highlight the fact that concerted proteolysis is essential for skin morphology and function. The cysteine protease cathepsin L (Ctsl) has been implicated in epidermal proliferation and desquamation, as well as in hair cycle regulation. In stark contrast, mice deficient in cathepsin B (Ctsb) do not display an overt skin phenotype. To understand the systematic consequences of deleting Ctsb or Ctsl, we determined the protein abundances of >1300 proteins and proteolytic cleavage events in skin samples of wild-type, Ctsb ؊/؊ , and Ctsl ؊/؊ mice via mass-spectrometry-based proteomics. Both protease deficiencies revealed distinct quantitative changes in proteome composition. Ctsl Cathepsins B and L are ubiquitously expressed papain-like cysteine proteases belonging to the C1a papain family (clan CA), with 11 members in humans (1) and 18 members in mice (2). Most cysteine cathepsins like cathepsin L are endopeptidases, whereas cathepsin B shows both endopeptidase and carboxydipeptidase activity (3). Mainly localized in the endosomal/lysosomal compartment, cathepsins have traditionally been thought to play important roles in lysosomal protein turnover. Additional specific functions have been postulated that link cathepsins to different physiological and pathological processes.Studies using cathepsin L (Ctsl)-gene-deficient mice 1 revealed an important role of Ctsl in cardiac homeostasis (4 -6) and a contribution of Ctsl to MHC II-mediated antigen presentation (7, 8) and prohormone processing (9, 10). In a mouse model of pancreatic neuroendocrine cancer, Ctsl promoted tumor growth and invasiveness (11,12). In stark contrast, Ctsl was found to attenuate tumor progression in mouse models of skin cancer, highlighting the context-specific function of this protease (13,14).The most prominent phenotype of Ctsl-deficient mice is periodic hair loss together with epidermal hyperplasia, acanthosis, and hyperkeratosis (15). These alterations in skin morphology are assumed to be keratinocyte specific, as controlled re-expression of Ctsl under a keratin 14 promoter Research

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“…Friedrichs et al (11) noted that this rather complex process involves sequential proteolytic events with some interaction with different cathepsins, B, K, and L (48). Covalently crosslinked Tg is stored in the thyroid follicular lumen where limited proteolysis occurs.…”

Section: Discussionmentioning

confidence: 99%

Revisiting Iodination Sites in Thyroglobulin with an Organ-oriented Shotgun Strategy

Dedieu

Gaillard

Pourcher³

et al. 2011

Journal of Biological Chemistry

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Thyroglobulin (Tg) is secreted by thyroid epithelial cells. It is essential for thyroid hormonogenesis and iodine storage. Although studied for many years, only indirect and partial surveys of its post-translational modifications were reported. Here, we present a direct proteomic approach, used to study the degree of iodination of mouse Tg without any preliminary purification. A comprehensive coverage of Tg was obtained using a combination of different proteases, MS/MS fragmentation procedures with inclusion lists and a hybrid mass highresolution LTQ-Orbitrap XL mass spectrometer. Although only 16 iodinated sites are currently known for human Tg, we uncovered 37 iodinated tyrosine residues, most of them being mono-or diiodinated. We report the specific isotopic pattern of thyroxine modification, not recognized as a normal peptide pattern. Four hormonogenic sites were detected. Two donor sites were identified through the detection of a pyruvic acid residue in place of the initial tyrosine. Evidence for polypeptide cleavages sites due to the action of cathepsins and dipeptidyl proteases in the thyroid were also detected. This work shows that semi-quantitation of Tg iodination states is feasible for human biopsies and should be of significant medical interest for further characterization of human thyroid pathologies.Thyroglobulin (Tg) 3 is one of the most abundant proteins produced by the thyroid gland and comprises two identical subunits of ϳ330 kDa. This prohormonal glycoprotein is secreted by thyroid epithelial cells. It is stored in the lumen of thyroid follicles in a highly condensed and covalently crosslinked form with numerous disulfide bridges. There, Tg is used as a scaffold for thyroid hormonogenesis and as an iodine reservoir. Many post-translational modifications are known to occur on this protein such as glycosylation, sulfation, and iodination (1). A signal peptide is processed during its export to the lumen. The most specific Tg post-translational modification is certainly its iodination and 3,5,3Ј-triiodothyronine (T3) and thyroxine (T4) thyroid hormone synthesis. Indeed, through the combined action of NADPH oxidase and thyroperoxidase on the outer surface of the thyrocyte apical membrane, iodide ions that are also transported to the follicular lumen are covalently linked to some Tg tyrosyl residues to form mono-or diiodotyrosines (MIT or DIT, respectively). Coupling of two of these DIT residues then leads to the formation of T4 at an acceptor site, whereas coupling one MIT and one DIT moiety essentially forms T3 (2). In this reaction, the release of an iodotyrosyl moiety at the donor site leaves an "empty" side chain and the fate of this unusual residue is controversial. Some authors claim that a dehydroalanine is left instead of the tyrosine, whereas others observed pyruvic acid associated with cleavage of the polypeptide chain (3-7). Finally, the protein is proteolytically processed in the lumen, followed by endocytosis in lysosomes, to release the hormones. The principal proteases involved inclu...

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Thyroid functions of mouse cathepsins B, K, and L

Cited by 194 publications

References 43 publications

Analysis of origin and growth of the thyroid gland in zebrafish

Analysis of origin and growth of the thyroid gland in zebrafish

Deletion of Cysteine Cathepsins B or L Yields Differential Impacts on Murine Skin Proteome and Degradome

Revisiting Iodination Sites in Thyroglobulin with an Organ-oriented Shotgun Strategy

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