Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy

Abstract

Mitophagy is a cellular quality-control pathway, which is essential for elimination of unhealthy mitochondria. While mitophagy is critical to pancreatic β-cell function, the posttranslational signals governing β-cell mitochondrial turnover are unknown. Here, we report that ubiquitination is essential for the assembly of a mitophagy regulatory complex, comprised of the E3 ligase Nrdp1, the deubiquitinase enzyme USP8, and Clec16a, a mediator of β-cell mitophagy with unclear function. We discover that the diabetes gene encodes an E3 ligase, which promotes nondegradative ubiquitin conjugates to direct its mitophagy effectors and stabilize the Clec16a-Nrdp1-USP8 complex. Inhibition of the Clec16a pathway by the chemotherapeutic lenalidomide, a selective ubiquitin ligase inhibitor associated with new-onset diabetes, impairs β-cell mitophagy, oxygen consumption, and insulin secretion. Indeed, patients treated with lenalidomide develop compromised β-cell function. Moreover, the β-cell Clec16a-Nrdp1-USP8 mitophagy complex is destabilized and dysfunctional after lenalidomide treatment as well as after glucolipotoxic stress. Thus, the Clec16a-Nrdp1-USP8 complex relies on ubiquitin signals to promote mitophagy and maintain mitochondrial quality control necessary for optimal β-cell function.

Clarifying the function of genes at the chromosome 16p13 locus in type 1 diabetes: CLEC16A and DEXI

“…Studies in mammalian systems also support a role for CLEC16A in the development of T1D. Indeed, we previously identified that CLEC16A maintains insulin secretion and glucose homeostasis by regulating the formation of a ubiquitin-dependent mitophagy complex within pancreatic β cells [7,8,10]. Beyond studies demonstrating a role for CLEC16A SNPs in human β-cell function, we also observed that pharmacological inhibition of the CLEC16Amitophagy pathway impaired β-cell function in humans [10].…”

“…1). Formerly known as KIAA0350, CLEC16A regulates mitochondrial autophagy and endosomal maturation [7][8][9][10]. CLEC16A is flanked by two neighboring genes: CIITA, which is required for the expression of MHC Class II, and SOCS1, a negative modulator of cytokine signaling.…”

“…Whereas in vivo functional studies of DEXI do not support a role in T1D, a dearth of studies in numerous models indicate crucial functional roles for CLEC16A. Originally thought to be a C-type lectin, CLEC16A in fact encodes an endolysosomal E3 ubiquitin ligase [10]. CLEC16A was first characterized in Drosophila to regulate endosomal trafficking and autophagosome function [18,19].…”

“…Indeed, we previously identified that CLEC16A maintains insulin secretion and glucose homeostasis by regulating the formation of a ubiquitin-dependent mitophagy complex within pancreatic β cells [7,8,10]. Beyond studies demonstrating a role for CLEC16A SNPs in human β-cell function, we also observed that pharmacological inhibition of the CLEC16Amitophagy pathway impaired β-cell function in humans [10]. Several recent studies have demonstrated key roles for CLEC16A in T-cell selection by modifying thymic epithelial autophagy as well as in NK cells, splenocytes, and Blymphocytes at least in part through mitophagy and/or MEK [7] signaling [21][22][23].…”

Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

“…CLEC16A plays a role in mitochondrial autophagy (mitophagy), a process to eliminate unhealthy mitochondria that is essential for maintaining beta-cell function, glucose homeostasis and GSIS (glucose-stimulated insulin secretion); inhibition of the CLEC16A-related pathway impairs beta-cell oxygen consumption and insulin secretion (98). A ubiquitin-dependent tripartite composed of CLEC16A, NRDP1, and USP18 was reported to act as a regulator of beta-cell mitophagy (99). A previous study found that pancreas-specific CLEC16A deficiency led to impaired glucose tolerance, ER stress and GSIS in mice, and a SNP in the CLEC16A gene (rs12708716) associated with reduced expression resulted in impaired beta-cell function in humans (98).…”