KDEL Receptors: Pathophysiological Functions, Therapeutic Options, and Biotechnological Opportunities
Articolo
Data di Pubblicazione:
2022
Abstract:
KDEL receptors (KDELRs) are ubiquitous seven-transmembrane domain proteins
encoded by three mammalian genes. They bind to and retro-transport endoplasmic reticulum (ER)-
resident proteins with a C-terminal Lys-Asp-Glu-Leu (KDEL) sequence or variants thereof. In doing
this, KDELR participates in the ER quality control of newly synthesized proteins and the unfolded
protein response. The binding of KDEL proteins to KDELR initiates signaling cascades involving
three alpha subunits of heterotrimeric G proteins, Src family kinases, protein kinases A (PKAs), and
mitogen-activated protein kinases (MAPKs). These signaling pathways coordinate membrane
trafficking flows between secretory compartments and control the degradation of the extracellular
matrix (ECM), an important step in cancer progression. Considering the basic cellular functions
performed by KDELRs, their association with various diseases is not surprising. KDELR mutants
unable to bind the collagen-specific chaperon heat-shock protein 47 (HSP47) cause the osteogenesis
imperfecta. Moreover, the overexpression of KDELRs appears to be linked to neurodegenerative
diseases that share pathological ER-stress and activation of the unfolded protein response (UPR).
Even immune function requires a functional KDELR1, as its mutants reduce the number of T
lymphocytes and impair antiviral immunity. Several studies have also brought to light the
exploitation of the shuttle activity of KDELR during the intoxication and maturation/exit of viral
particles. Based on the above, KDELRs can be considered potential targets for the development of
novel therapeutic strategies for a variety of diseases involving proteostasis disruption, cancer
progression, and infectious disease. However, no drugs targeting KDELR functions are available to
date; rather, KDELR has been leveraged to deliver drugs efficiently into cells or improve antigen
presentation.
Tipologia CRIS:
1.1 Articolo in rivista
Keywords:
endoplasmic reticulum homeostasis; chaperones retrieval; unfolded protein response;
viruses trafficking; targeted therapies
Elenco autori:
Cela, Ilaria; Dufrusine, Beatrice; Rossi, Claudia; Luini, Alberto; De Laurenzi, Vincenzo; Federici, Luca; Sallese, Michele
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