The p41 isoform of invariant chain is a chaperone for cathepsin L

Lennon-Duménil, Ana-María; Roberts, Rebecca; Valentijn, Karine M.; Driessen, Christoph; Overkleeft, Herman S.; Erickson, Ann H.; Peters, Peter J.; Bikoff, Elizabeth K.; Ploegh, Hidde L.; Bryant, Paula Wolf

doi:10.1093/emboj/20.15.4055

Cited by 67 publications

(71 citation statements)

References 48 publications

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“…Thus, the inhibitor p41 acts as a chaperone, maintaining a pool of mature cathepsin L in the endocytic compartment for antigen processing (73). In the absence of this chaperone, mature cathepsin L is degraded with faster kinetics (73). Moreover, the double-chain form of cathepsin L in some antigen-presenting cells is inactive (74), similar to that observed for cathepsin B in the studies reported here.…”

Section: Discussionsupporting

confidence: 76%

“…In antigen-presenting cells, the p41 splice variant of the invariant chain inhibits cathepsin L (72,73). In cells lacking p41, steady-state levels of the double-chain form of cathepsin L are decreased.…”

Section: Discussionmentioning

confidence: 99%

“…In cells lacking p41, steady-state levels of the double-chain form of cathepsin L are decreased. Thus, the inhibitor p41 acts as a chaperone, maintaining a pool of mature cathepsin L in the endocytic compartment for antigen processing (73). In the absence of this chaperone, mature cathepsin L is degraded with faster kinetics (73).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Cathepsin B Is Inhibited in Mutant Cells Selected during Persistent Reovirus Infection

Ebert

Kopecky-Bromberg

Dermody

2004

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cathepsin B Is Inhibited in Mutant Cells Selected during Persistent Reovirus Infection

Ebert

Kopecky-Bromberg

Dermody

2004

Journal of Biological Chemistry

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“…Recent observations have linked Cat L stability to a chaperone-like activity of the Ii chain alternatively spliced product p41 (30). p41 was detected neither in HeLa-CIITA cells (INF-␥-treated or not), nor in MelJuSo cells (Fig.…”

Section: Which Human Cathepsin Is Responsible For P10 Degradation?mentioning

confidence: 92%

Human cathepsin S, but not cathepsin L, degrades efficiently MHC class II-associated invariant chain in nonprofessional APCs

Bania

Gatti

Lelouard

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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MHC class II-restricted antigen presentation plays a central role in the immune response against exogenous antigens. The association of invariant (Ii) chain with MHC class II dimers is required for proper antigen presentation to CD4 ؉ T cells by antigen-presenting cells. MHC class II complexes first traffic through the endocytic pathway to allow Ii chain degradation and antigenic peptide loading before their arrival at the cell surface. In recent years, a considerable effort has been directed toward the identification of proteases responsible for Ii chain degradation. Targeted gene deletion in mice has allowed a precise description of the cysteine proteases involved in the last step of Ii chain degradation. By using nonspecialized cellular models expressing MHC II molecules, we are now exploring the contribution of known cysteine proteases to human Ii chain processing. Surprisingly and contrary to the situation in mouse, cathepsin S was found to be the only human cysteine protease able to efficiently degrade the Ii-p10 fragment in epithelial cells. This selectivity has implications for thymic selection and indicates that differences between man and mice are probably more profound at this level than expected.antigen presentation ͉ lysosome ͉ protease

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“…However, the net effect of p41 on cathepsin L activity remains unresolved since it also acts as a cathepsin L chaperone and increases active cathepsin L protein levels in bone marrow macrophages [22]. Nonetheless, the ability of p41 to attenuate protease activity may account, at least in part, for its ability to enhance antigen presentation given that proteases can occassionally destroy T cell epitopes as discussed below [23].…”

Section: Antigen Processing and Presentationmentioning

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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The p41 isoform of invariant chain is a chaperone for cathepsin L

Cited by 67 publications

References 48 publications

Cathepsin B Is Inhibited in Mutant Cells Selected during Persistent Reovirus Infection

Cathepsin B Is Inhibited in Mutant Cells Selected during Persistent Reovirus Infection

Human cathepsin S, but not cathepsin L, degrades efficiently MHC class II-associated invariant chain in nonprofessional APCs

Diverse regulatory roles for lysosomal proteases in the immune response

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