|Coordinate||64,366,623 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||cathepsin L|
|Synonym(s)||major excreted protein, 1190035F06Rik, Cat L, MEP|
|Chromosomal Location||64,359,337-64,370,890 bp (-)|
FUNCTION: This gene encodes a member of the peptidase C1 (papain) family of cysteine proteases. The encoded preproprotein is proteolytically processed to generate multiple protein products. These products include the activation peptide and the cathepsin L1 heavy and light chains. The mature enzyme appears to be important in embryonic development through its processing of histone H3 and may play a role in disease progression in a model of kidney disease. Homozygous knockout mice for this gene exhibit hair loss, skin thickening, bone and heart defects, and enhanced susceptibility to bacterial infection. A pseudogene of this gene has been identified in the genome. [provided by RefSeq, Aug 2015]
PHENOTYPE: Homozygotes for mutant alleles may show partial or complete hair-loss, skin defects, impaired T cell maturation, dilated cardiomyopathy, and high postnatal mortality. Mutant males for some alleles show both normal and atrophic seminiferous tubules and reduced sperm production. [provided by MGI curators]
|Amino Acid Change||Arginine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000021933] [ENSMUSP00000152551] [ENSMUSP00000152497] [ENSMUSP00000152169] [ENSMUSP00000152357]|
AA Change: R214*
|Predicted Effect||probably null|
|Predicted Effect||probably benign|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||0.9704|
|Is this an essential gene?||Essential (E-score: 1.000)|
|Candidate Explorer Status||CE: good candidate; Verification probability: 0.983; ML prob: 0.9832; human score: -3|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Local Stock||Live Mice|
|Last Updated||2021-03-22 4:00 PM by External Program|
|Record Created||2019-02-08 12:20 PM by Jamie Russell|
The patch phenotype was identified among G3 mice of the pedigree R6725, some of which showed sparse hair growth and/or alopecia all over their bodies (Figure 1). Some mice also showed decreased CD4 to CD8 T cell ratios (Figure 2), and reduced frequencies of T cells (Figure 3), CD4+ T cells (Figure 4), CD4+ T cells in CD3+ T cells (Figure 5), and naïve CD4 T cells in CD4 T cells (Figure 6) with concomitant increased frequencies of CD44+ T cells (Figure 7), CD44+ CD8 T cells (Figure 8), CD8+ T cells (Figure 9), CD8+ T cells in CD3+ T cells (Figure 10), central memory CD4 T cells in CD4 T cells (Figure 11), central memory CD8 T cells in CD8 T cells (Figure 12), and effector memory CD4 T cells in CD4 T cells (Figure 13), all in the peripheral blood. The mice showed increased CD44 expression on peripheral blood T cells (Figure 14), CD4+ T cells (Figure 15), and CD8+ T cells (Figure 16).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 54 mutations. The hair growth phenotype was linked to a mutation in Ctsl: an A to T transversion at base pair 64,366,623 (v38) on chromosome 13, or base pair 4,126 in the GenBank genomic region NC_000079. The strongest association was found with a recessive model of inheritance to the reduced CD4+ T cell in CD3+ T cell frequency phenotype, wherein 18 variant homozygotes departed phenotypically from 19 homozygous reference mice and 39 heterozygous mice with a P value of 7.975 x 10-32 (Figure 17). A substantial semidominant effect was also observed for most of the assays, but the mutation is preponderantly recessive.
The mutation corresponds to residue 936 in the mRNA sequence NM_009984 within exon 6 of 8 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of arginine (R) 214 for a premature stop codon (R214*) in the CTSL protein.
|Illustration of Mutations in
Gene & Protein
Ctsl encodes cathepsin L, one of 11 cysteine protease cathepsins (i.e., cathepsins B, C, F, H, K, L, O, S (see the record for clip, V, W, and X). The cysteine cathepsins are members of the papain family.
Human liver cathepin L is comprised of a 25-kDa heavy chain and a 5-kDa light chain (Figure 18) (1). Cathepsin L has a 17-amino acid signal sequence and a 96-amino acid propeptide that is not present in the heavy chain in the mature protein (2,3). Procathepsin L is processed to mature cathepsin L through cleavage of the propeptide in the lysosome (4).
Cathepsin L folds similar to other members of the papain superfamily [Figure 19; PDB:1CJL; (5)]. Cathepsin L has two domains delimiting an active-site cleft containing the catalytic Cys25 and His163 residues; Cys25 is within the mostly α-helical domain, while His163 is within the mostly β-sheet domain. The propeptide region of cathepsin L has three segments: a globular domain, an active cleft-binding segment, and a flexible C-terminal segment (5). The globular domain is comprised of the intersecting α (α1 and α2) helices and the β1 strand. The β1 strand, running antiparallel to the α2 helix, interacts with the proregion binding loop of the mature enzyme. The proregion is required for proper protein folding, stability, and for exit from the endoplasmic reticulum (6). The proregion contacts cathepsin L along the substrate binding cleft and along the surface formed by the His140—Asp155 loop (5). Cathepsin L has a conserved α-helical motif (ER(F/W)N(I/V)N) within the α2 helix of the proregion that is essential for its proper folding, transport, and maturation (7). The C-terminus of cathepsin L is required for its secretion, but not for its enzyme activity, posttranslational processing, or subcellular distribution (8). Serine, proline, and valine residues within the last six amino acids of the C-terminal tail are required for cathepsin L secretion.
Human CTSL produces two mRNAs (CATLA and CATLB) that differ in the 5’-UTR (9). The two mRNAs are putatively generated through the use of alternative splicing or the presence of a second promoter within the first intron of CTSL. The functional significance of the two mRNAs is unknown. CATLB was expressed at higher levels than CATLA in all human cell lines examined. A second study cloned three CTSL variants: CATLA, CATLA2, and CATLA3; the CATLB variant could not be cloned (10). The CATLA, CATLA2, and CATLA3 variants differed in the length of exon 1. The CATLA3 variant was predominantly expressed in all tissues and cells examined. A third study found four splice variants (CATLA, CATLA1, CATLA2, and CATLA3) in several human tumor cell lines (11). All variants had identical open reading frames, but differed in the 5’-UTR. A fourth study found two human CTSL splice variants designated CATL-A I and CATL-A II, which lack 27-base pairs and 90-base pairs from exon 1, respectively (12). The splice variants do not affect the translated product.
The patch mutation results in substitution of arginine (R) 214 for a premature stop codon (R214*); residue 214 is within the cathepsin L heavy chain; the mutation is predicted to affect both the heavy and light chains.
Cathepsin L is ubiquitously expressed. In rats, cathepsin L is highly expressed in the kidney, with lower expression in the liver, spleen, lungs, brain and cerebellar cortex, and low expression in the heart, skeletal muscle, gastrointestinal tract, and peripheral blood cells (13).
Cathepsin L is a cysteine protease. A cysteine protease hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. Hydrolysis involves usually a catalytic triad consisting of the thiol group of the cysteine, the imidazolium ring of a histidine, and a third residue, usually asparagine or aspartic acid, to orientate and activate the imidazolium ring.
Cathepsin L promotes the cleavage of several target proteins (Table 1), functioning in numerous physiological and pathological processes, including thyroid hormone processing, arthritis, osteoporosis, bone resorption, and cancer. Cathepsin L is essential for matrix degradation, invasion of circulating endothelial progenitor cells into ischemic tissue, and endothelial progenitor cell-mediated neovascularization (14).
Table 1. Select cathepsin L targets
In humans, cathepsin L is linked to myofibril necrosis in myopathies and in myocardial ischemia, and in the renal tubular response to proteinuria (2). Cathepsin L activity is elevated in chronic kidney disease patients, indicating that serum levels of cathepsin L may be a biomarker for the disease (41). Cathepsin L and cathepsin B activity is also increased in peripheral blood mononuclear cells from patients with dilated cardiomyopathy (42). Increased levels of both cathepsin L and cathepsin B correlated with reduced left ventricular ejection fraction in the patients.
Thymocytes develop into T cells in the thymus through interactions with cortical thymic epithelial cells (cTECs). CD4+/CD8+ double positive thymocytes undergo both positive and negative selection based on the strength of the interaction between the T cell receptor (TCR) and the major histocompatibility complex (MHC) of cTECs. If the interaction is too weak, T cells undergo death by neglect and if the interaction is too strong, T cells undergo negative selection. Interactions in a narrow range of affinities lead to positive selection and survival of the thymocytes (43–45). The strength of this interaction is determined by the antigens loaded on the MHCs.
cTECs express cathepsin L (Ctsl) and undergo a high rate of constitutive macroautophagy (46). Macroautophagy is carried out by cathepsin L and the thymus-specific serine protease Prss16 to generate self-peptides which are loaded onto MHC II receptors (47–50). MHC I complexes undergo a similar antigen loading process where peptides are generated by the proteasome β5t (Psmb11) (51).
MHC II receptors are αβ heterodimers which are assembled with the assistance of the invariant (Ii) chain. The Ii chain functions as a chaperone and is crucial for targeting the MHC II receptor to the lysosome, where the Ii chain is degraded by cathepsin L and antigens are loaded onto the MHC II receptor before it is transported to the plasma membrane to interact with TCRs (15,16).
Mice homozygous for null alleles exhibited alopecia, short hair length, dull greasy coats, short and sparse vibrissae, increased keratinocyte proliferation, aberrant hair cycling, epidermal hyperplasia, thick epidermis, reduced CD4+ T cell numbers, increased regulatory T cell numbers, reduced NK T cells, reduced osteoclast numbers, dermatitis, folliculitis, disorganized mineralized cartilage zone, and reduced amounts of trabecular bone (52–56). Some Ctsl-deficient mice showed reduced viability before weaning, enlarged hearts, cardiac interstitial fibrosis, dilated cardiomyopathy, increased heart rates, prolonged intervals between the R- and T-waves of an electrocardiogram, and increased thyroglobulin levels (57–60). Mice homozygous for a spontaneous single-point mutation (Ctslfs/fs; p.R149G) showed reduced viability before weaning as well as alopecia and absent vibrissae (61,62). Although fertile, some male Ctslfs/fs mice showed reduced testis weights, atrophic seminiferous tubules, reduced formation of preloptotene spermatocytes in normal tubules, and reduced differentiation of preloptotene spermatocytes into pachytene spermatocytes in normal tubules (63). Mice homozygous for a radiation-induced 118-base pair deletion in exons 6 and 7 (Ctslnkt/nkt) showed runting, delayed hair appearance, aberrant hair follicle development, sparse hair, alopecia, epidermal hyperplasia, excessive scratching, dermatitis, skin lesions, enlarged sebaceous glands, enlarged lymph nodes, enlarged thymus cortex, corneal opacity, areas of periodontal ligament and dental pulp necrosis, reduced numbers of CD4+ T cells with concomitant increased numbers of CD8+ T cells (64–67). Ctslnkt/nkt pups suckled by either a heterozygous or homozygous dam showed lethality by 3 weeks or 10 days, respectively (64).
Cathepsin L is required for proper hair follicle morphogenesis and cycling as well as for proper epidermal differentiation (Figure 20) (56,66). Ctsl-deficient mice showed disruption in the exiting of hair shafts to the skin surface primarily due to a failure of the inner root sheath to fully desquamate, dilation of the hair canal, and abnormal routing of sebaceous gland products to the skin surface (56).
The hair loss phenotype observed in the patch mice indicates loss of cathepsin-associated function.
Mice lacking Ctsl have been reported to have severely impaired CD4+ T cell populations (47,65,68). This has been demonstrated to be through both failure to degrade the Ii chain and an inability to generate self-peptides (46–50). MHC II receptors are then unable to bind TCRs, leading to reduced positive selection and causing thymocytes to undergo excessive death by neglect (69–71).
No phenotypic mutations are listed in the Mutagenetix database for Prss16, Psmb5, Psmb8, or Psmb11.
1) 94°C 2:00
The following sequence of 401 nucleotides is amplified (chromosome 13, - strand):
1 ggctttgttt tcagaaaagg aagcattacc agatgtggtt ttcagagttc atactttagt
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
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|Science Writers||Anne Murray, Thomas Gallagher|
|Authors||Jamie Russell, Jin Huk Choi, Xue Zhong, Andon Arnold, Carlos Reyna, Dana Smith, Lauren Prince, and Bruce Beutler|