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Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

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Abstract

Proteases play essential roles in protein degradation, protein processing, and extracellular matrix remodeling in all cell types and tissues. They are also involved in protein turnover for maintenance of homeostasis and protein activation or inactivation for cell signaling. Proteases range in function and specificity, with some performing distinct substrate cleavages, while others accomplish proteolysis of a wide range of substrates. As such, different cell types use specialized molecular mechanisms to regulate the localization of proteases and their function within the compartments to which they are destined. Here, we focus on the cysteine family of cathepsin proteases and legumain, which act predominately within the endo-lysosomal pathway. In particular, recent knowledge on cysteine cathepsins and their primary regulator legumain is scrutinized in terms of their trafficking to endo-lysosomal compartments and other less recognized cellular locations. We further explore the mechanisms that regulate these processes and point to pathological cases which arise from detours taken by these proteases. Moreover, the emerging biological roles of specific forms and variants of cysteine cathepsins and legumain are discussed. These may be decisive, pathogenic, or even deadly when localizing to unusual cellular compartments in their enzymatically active form, because they may exert unexpected effects by alternative substrate cleavage. Hence, we propose future perspectives for addressing the actions of cysteine cathepsins and legumain as well as their specific forms and variants. The increasing knowledge in non-canonical aspects of cysteine cathepsin- and legumain-mediated proteolysis may prove valuable for developing new strategies to utilize these versatile proteases in therapeutic approaches.

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Acknowledgments

The work of our groups was supported by grants from the Deutsche Forschungsgemeinschaft [BR 1308/6-1 to 6-2, 7-1 to 7-3, 10-1, 11-1] and the South-East regional health authorities [HSØ, #2011142].

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The authors declare that no conflict of interest exists.

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Authors and Affiliations

  1. Research Area HEALTH, Research Center MOLIFE—Molecular Life Sciences, Jacobs University Bremen, Campus Ring 1, 28759, Bremen, Germany

    Klaudia Brix, Joseph McInnes, Alaa Al-Hashimi, Maren Rehders, Tripti Tamhane & Mads H. Haugen

  2. Department of Human Genetics, KU Leuven, Leuven, Belgium

    Joseph McInnes

  3. Institute for Cancer Research, Oslo University Hospital—Norwegian Radium Hospital, Oslo, Norway

    Mads H. Haugen

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  1. Klaudia Brix
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  2. Joseph McInnes
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  3. Alaa Al-Hashimi
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Correspondence to Klaudia Brix.

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Brix, K., McInnes, J., Al-Hashimi, A. et al. Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges. Protoplasma 252, 755–774 (2015). https://doi.org/10.1007/s00709-014-0730-0

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