Abstract
The ligand of Numb protein-X (LNX) family, also known as the PDZRN family, is composed of four discrete RING-type E3 ubiquitin ligases (LNX1, LNX2, LNX3, and LNX4), and LNX5 which may not act as an E3 ubiquitin ligase owing to the lack of the RING domain. As the name implies, LNX1 and LNX2 were initially studied for exerting E3 ubiquitin ligase activity on their substrate Numb protein, whose stability was negatively regulated by LNX1 and LNX2 via the ubiquitin-proteasome pathway. LNX proteins may have versatile molecular, cellular, and developmental functions, considering the fact that besides these proteins, none of the E3 ubiquitin ligases have multiple PDZ (PSD95, DLGA, ZO-1) domains, which are regarded as important protein-interacting modules. Thus far, various proteins have been isolated as LNX-interacting proteins. Evidence from studies performed over the last two decades have suggested that members of the LNX family play various pathophysiological roles primarily by modulating the function of substrate proteins involved in several different intracellular or intercellular signaling cascades. As the binding partners of RING-type E3s, a large number of substrates of LNX proteins undergo degradation through ubiquitin-proteasome system (UPS) dependent or lysosomal pathways, potentially altering key signaling pathways. In this review, we highlight recent and relevant findings on the molecular and cellular functions of the members of the LNX family and discuss the role of the erroneous regulation of these proteins in disease progression.
Highlights
Protein ubiquitylation, which is a highly conserved post-translational modification in which ubiquitin is covalently linked to lysine residues of a substrate protein, is associated with most aspects of eukaryotic physiology
The E3 ubiquitin ligase activity of human LNX2, unlike that of LNX1, has been addressed relatively recently, after its ability to bind to the T-cell co-receptor CD8 α-chain (CD8α) via the cytoplasmic
A recent finding showed that LNX1 suppressed the aggravation of tuberculosis, an infectious disease caused by Mycobacterium tuberculosis [31]
Summary
Protein ubiquitylation, which is a highly conserved post-translational modification in which ubiquitin (consisting of 76 amino acids) is covalently linked to lysine residues of a substrate protein, is associated with most aspects of eukaryotic physiology. Among the five members of the LNX family (LNX1-LNX5), LNX1-LNX4 may function as E3 ubiquitin ligases that target miscellaneous substrates for ubiquitylation, as these possess a RING domain with multiple PDZ (PSD95, DLGA, ZO-1) domains, each of which are considered protein-protein interacting modules [9,10,11,12,13]. The intramolecular loop of the C-terminal class I PDZ-binding motifs could have bound to the second PDZ domains (class I PDZ domain is able to bind S/T-X-C) of LNX1 and LNX2 [15] Their intrinsic E3 ubiquitin ligase functions were regulated at the intramolecular level, and could be further modulated by post-translational modifications, such as by the attachment of phosphate moieties.
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