A Cathepsin L Isoform that Is Devoid of a Signal Peptide Localizes to the Nucleus in S Phase and Processes the CDP/Cux Transcription Factor

Goulet, Brigitte; Baruch, Amos; Moon, Nam-Sung; Poirier, Madeleine; Sansregret, Laurent; Erickson, Ann H.; Bogyo, Matthew; Nepveu, Alain

doi:10.1016/s1097-2765(04)00209-6

Cited by 331 publications

(345 citation statements)

References 34 publications

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“…The specific cathepsin L inhibitor Z-FY-CHO inhibited cathepsin L-mediated cleavage of purified and nuclear topo I (Figures 3C and D). The concentration ranges of cathepsins and the incubation conditions used in these experiments were based on reported studies (26,27). It should be noted that untreated topo I, either in purified form or in the isolated nuclei, underwent limited degradation into a 70-kd product during protein or nuclear preparation (Figure 3), consistent with previous reports (3)(4)(5).…”

Section: Resultssupporting

confidence: 85%

“…Cleavage reactions with cathepsin L conducted at an optimal pH of 5.5 yielded a cleavage profile identical to that observed at neutral pH. Although optimal enzymatic activity by cathepsins is achieved at pH 5.5, Goulet et al (27) demonstrated recently that cathepsin L is active and can process substrates at neutral pH. Those investigators suggested that the suboptimal pH of 7.5 should not be taken as an obstacle but as a key element that enables cathepsin L and perhaps other cathepsins to play an important role in the limited protein cleavage outside the lysosomes, particularly in the nucleus.…”

Section: Discussionmentioning

confidence: 79%

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Involvement of lysosomal cathepsins in the cleavage of DNA topoisomerase I during necrotic cell death

Pacheco¹,

Servin²,

Dang³

et al. 2005

Arthritis & Rheumatism

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Objective. Autoantibodies to DNA topoisomerase I (topo I) are associated with diffuse systemic sclerosis (SSc), appear to be antigen driven, and may be triggered by cryptic epitopes exposed during in vivo topo I fragmentation. These autoantibodies recognize topo I and fragments of this autoantigen generated during apoptosis and necrosis. We undertook this study to determine whether lysosomal cathepsins are involved in topo I fragmentation during necrosis.Methods. Topo I cleavage during necrosis was assessed by immunoblotting of lysates from L929 fibroblasts exposed to tumor necrosis factor ␣ (

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Section: Resultssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 79%

Involvement of lysosomal cathepsins in the cleavage of DNA topoisomerase I during necrotic cell death

Pacheco¹,

Servin²,

Dang³

et al. 2005

Arthritis & Rheumatism

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“…In mid-G1 phase, 1% to 5% of p200 CUX1 is proteolytically processed to generate p110 CUX1, which contains the last two CUT repeats and the CUT HD (CR2-CR3-HD) 25,40 . This isoform, although produced .…”

Section: Non-oncogene Addictionsmentioning

confidence: 99%

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

2014

Self Cite

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“…How AEP or other endocytic proteases might access the cytosol/nuclear compartments is not known. Cathepsin L is also detected in the nucleus of some cells at the G1/S cell cycle transition and processes the transcriptional regulator CCAAT displacement protein (CDP)/Cux into a form with enhanced DNA binding and that promotes cell cycle progression [89]. Compartmental reassignment of cathepsin L is achieved through translation initiation at alternative start codons downstream of the normal signal sequence (Fig.…”

Section: Cytosolic and Nuclear Substrates Of Lysosomal Proteasesmentioning

confidence: 99%

“…1D). Interestingly, nuclear fractions appeared to contain not only the single chain but also the heavy chain of the two-chain form of cathepsin L [89]. How this signal sequence deficient form of cathepsin L is Eur.…”

Section: Cytosolic and Nuclear Substrates Of Lysosomal Proteasesmentioning

confidence: 99%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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The innate and adaptive immune system utilise endocytic protease activity to promote functional immune responses. Cysteine and aspartic proteases (cathepsins) constitute a subset of endocytic proteases, the immune function of which has been described extensively. Although historically these studies have focused on their role in processes such as antigen presentation and zymogen processing within the endocytic compartment, recent discoveries have demonstrated a critical role for these proteases in other intracellular compartments, and within the extracellular milieu. It has also become clear that their pattern of expression and substrate specificities are more diverse than was first envisaged. Here, we discuss recent advances addressing the role of lysosomal proteases in various aspects of the immune response. We pay attention to reports demonstrating cathepsin activity outside of its canonical endosome/lysosome microenvironment.Key words: Cathepsins . Endosomes . Immune regulation . Lysosomes IntroductionThe endosome/lysosome compartments, together with the cytosolic proteasomes, are the two major protein degradation systems in cells. Both have emerged as having many important regulatory functions in addition to their role in protein breakdown for amino acid recycling. For example, limited proteolysis within the endocytic pathway can induce activating conformational changes [1,2], release functional proteins from chaperones [3], and cleave soluble bioactive molecules from membrane-anchored precursors [4]. The concept of ''regulation through limited destruction'' is evident in many processes in innate and adaptive immunity. Endosome/lysosome-located proteases play key roles in antigen processing and presentation, cytokine regulation, NKT cell development, activation of serine protease zymogens in regulated secretory granules, integrin activation, induction of apoptosis and TLR signalling. Given that these processes may also be associated with undesirable immune responses and inflammation, the proteases involved may be considered as attractive drug targets. EnzymesEndosomes and lysosomes harbour mainly cysteine and aspartic acid proteases so-named because their active site utilises either a cysteine thiol or an aspartic acid as a key part of the catalytic site. Some endosome/lysosome located serine proteases such as cathepsin G, granzymes and thymus specific serine protease (TSSP) have important roles in the immune system; however, we focus primarily here on the cysteine and aspartic proteases. Most of the lysosomal cysteine proteases are related to papain and belong to the so-called C1 family. These include cathepsins L, S, C, F, H, B, X, K, V and W. Cathepsins D and E are also found in lysosomes but are aspartic acid proteases related to pepsin. An additional cysteine protease is found in lysosomes, which is more closely related to the caspases. This is asparaginyl endopeptidase (AEP) or legumain, a member of the C13 family. Some of these enzymes are endopeptidases (cathepsins S, L, K, F, V, D, E and AEP), where...

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A Cathepsin L Isoform that Is Devoid of a Signal Peptide Localizes to the Nucleus in S Phase and Processes the CDP/Cux Transcription Factor

Cited by 331 publications

References 34 publications

Involvement of lysosomal cathepsins in the cleavage of DNA topoisomerase I during necrotic cell death

Involvement of lysosomal cathepsins in the cleavage of DNA topoisomerase I during necrotic cell death

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

Diverse regulatory roles for lysosomal proteases in the immune response

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