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

Area of Science:

• Cellular Biology
• Molecular Biology
• Endocrinology

Background:

• Mitophagy is crucial for pancreatic beta-cell health and function.
• The posttranslational signals controlling beta-cell mitochondrial turnover remain largely unknown.

Purpose of the Study:

• To investigate the role of ubiquitination in regulating beta-cell mitophagy.
• To identify key components of the mitophagy regulatory complex in beta-cells.

Main Methods:

• Investigated the E3 ligase Nrdp1, deubiquitinase USP8, and Clec16a in beta-cell mitophagy.
• Utilized lenalidomide, a ubiquitin ligase inhibitor, to assess pathway inhibition.
• Examined the impact of pathway inhibition on beta-cell function, oxygen consumption, and insulin secretion.

Main Results:

• Discovered Clec16a as an E3 ligase that stabilizes the Clec16a-Nrdp1-USP8 complex via nondegradative ubiquitin conjugates.
• Lenalidomide treatment impaired beta-cell mitophagy, oxygen consumption, and insulin secretion.
• The Clec16a-Nrdp1-USP8 complex was destabilized by lenalidomide and glucolipotoxic stress, correlating with compromised beta-cell function in patients.

Conclusions:

• Ubiquitination is essential for assembling the Clec16a-Nrdp1-USP8 complex, which governs beta-cell mitophagy.
• This complex is vital for maintaining mitochondrial quality control and optimal beta-cell function.
• Dysfunction of this complex contributes to impaired beta-cell function observed in lenalidomide-treated patients and under stress conditions.