Abstract
p62/SQSTM1 (sequestosome-1) is a key protein involved in multiple cellular bioprocesses including autophagy, nutrient sensing, cell growth, cell death, and survival. Therefore, it is implicated in human diseases such as obesity and cancer. Here, we show that the CUL5–ASB6 complex is a ubiquitin E3 ligase complex mediating p62 ubiquitination and degradation. Depletion of CUL5 or ASB6 induced p62 accumulation, and overexpression of ASB6 promoted ubiquitination and degradation of p62. Functionally, ASB6 overexpression can inhibit the proliferation of MEF and hepatocellular carcinoma cells by reducing p62 protein level, and impair the occurrence of autophagy. Overall, our study identified a new molecular mechanism regulating p62 stability, which may provide additional insights for understanding the delicate control of p62 and cell proliferation–autophagy control in physiological and pathological settings.
Highlights
P62, encoded by SQSTM1 gene, is the first discovered autophagic adaptor protein, which participates in many cellular processes, such as cell growth and proliferation, autophagy, malignant transformation, apoptosis, and inflammation (Layfield and Hocking, 2004; McManus and Roux, 2012; Moscat and Diaz-Meco, 2012)
The interaction between p62 and Elongin C (EloC) was stronger than the p62–Elongin B (EloB) interaction. These results indicated that p62 is a potential CRL5 ubiquitination substrate, since the substrate recognition subunit of CRL5 directly interacts with the linker protein EloC via the SOCS-box region and indirectly interacts with EloB via N-terminus of CUL5 protein
ASB6 overexpression inhibited the colony formation and cell proliferation of ATG7−/− MEF cells (Figures 5C,D). These results suggest that the regulation of p62 by the CUL5–ASB6 complex does not depend on the occurrence of autophagy process
Summary
P62, encoded by SQSTM1 gene, is the first discovered autophagic adaptor protein, which participates in many cellular processes, such as cell growth and proliferation, autophagy, malignant transformation, apoptosis, and inflammation (Layfield and Hocking, 2004; McManus and Roux, 2012; Moscat and Diaz-Meco, 2012). The E3 ubiquitin ligase Parkin directly interacts with and ubiquitinates p62 to promote proteasomal degradation of p62, and dysregulation of Parkin/p62 axis could account for the selective vulnerability during pathogenesis of PD (Song et al, 2016) Another recent study has shown that X-linked inhibitor of apoptosis protein (XIAP) functioned as a ubiquitination E3 ligase toward p62 and suppressed p62 expression through ubiquitinproteasomal degradation and promoted breast cancer progression (Huang et al, 2019). We found that a functional Cullin-Ring E3 ligase (CRL) complex composed of Cullin (CUL5), Elongin B (EloB), Elongin C (EloC), and substrate recognition adaptor ASB6 interacts with p62 and mediates its ubiquitination-dependent degradation. Our study has characterized a new functional CRL5–ASB6 E3 complex, and identified p62 as the first degradation substrate of it, which may provide new insight for cell proliferation and autophagy regulation
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