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

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.

Overexpression of asparaginyl endopeptidase is significant for esophageal carcinoma metastasis and predicts poor patient prognosis

“…AEP is reported to be overexpressed in multiple types of human solid tumors and acute lymphoblastic leukemia compared with normal tissues (16)(17)(18)(19)(20)(21). In the present study, it was demonstrated that AEP mRNA and protein levels were increased in EC109 and TE-1 esophageal cancer cell lines.…”

“…Previous studies have revealed that AEP is localized in the front of invading cells, and forms a complex with integrins on the surface of lamellipodia and invadopodia (17). The binding of AEP to integrins significantly promotes its ability to activate pro-MMP2 and cathepsin L (25).…”

“…AEP has been demonstrated to contribute important functions in kidney physiology, immunity, atherogenesis and bone metabolism (9)(10)(11)(12)(13)(14)(15). In previous years, high AEP expression has been observed in a variety of solid tumors and acute lymphoblastic leukemia (16)(17)(18)(19)(20)(21). Furthermore, AEP expression positively correlated with clinicopathological and biological variables in colorectal, and breast cancer (19,20).…”

“…Furthermore, AEP expression positively correlated with clinicopathological and biological variables in colorectal, and breast cancer (19,20). Although cancer cells that highly express AEP have been revealed to exhibit enhanced migratory and invasive capacity through the activation of pro-matrix-metalloproteinase 2 (MMP2), and cathepsins (17,22,23), the pathological functions and underlying mechanisms of AEP in esophageal cancer remain elusive.…”

From information to knowledge

“…However, as shown exemplarily for cathepsins and legumain (Brix et al 2015), a deeper mechanistic understanding of the cellular aspects can contribute to design applications more efficiently. To bridge the gap between animal cell biology and medical application, clear concepts are highly relevant, which was one of the motivations to nominate a review editor for the field of animal and medical cell biology.…”