# The Degradation Pathway of COP9 Signalosome–Cullin-RING Ubiquitin Ligase Complexes via Autophagy

## TL;DR

This study reveals that specific COP9 signalosome-Cullin-RING complexes are degraded through autophagy, a process that can be inhibited by certain drugs.

## Contribution

The study identifies self-ubiquitylation of cullins as a signal for selective macroautophagy of CSN-CRL complexes.

## Key findings

- CSNCSN7A-CRL3 and CSNCSN7B-CRL4A complexes are degraded via autophagy in the absence of serum.
- Self-ubiquitylation of cullins acts as a signal for selective macroautophagy of CSN-CRL complexes.
- CSN-CRL complexes are expelled from the nucleus and localized in autophagosomes for degradation.

## Abstract

In Mammalia, the COP9 signalosome (CSN) is associated with cullin-RING ubiquitin ligases (CRLs). This study focuses on the variants CSNCSN7A and CSNCSN7B, which form complexes with CRL3 and CRL4A, respectively. Although some research has been conducted on the assembly of the complexes, little is known about their breakdown. Here, we show that entire CSNCSN7A-CRL3 and CSNCSN7B-CRL4A complexes are degraded via autophagy. CSN-CRL complexes are degraded in the absence of serum via bulk autophagy and in the presence of the specific inhibitor of CSN, CSN5i-3, via selective macroautophagy. Surprisingly, the self-ubiquitylation of cullins in the CRLs was identified as a specific signal for selective macroautophagy. The self-ubiquitylation of cullins takes place in the presence of CSN5i-3, and CSN-CRL complexes are expelled from the nucleus to be degraded in the cytosol. Selective macroautophagy can be blocked by chloroquine, a specific inhibitor of autophagy. Interestingly, the process can also be inhibited by MLN4924, a neddylation inhibitor. Confocal fluorescence microscopy illustrates the interaction of CSN subunits with ATG8, as well as with RAB7, both in HeLa and in LiSa-2 cells. Confocal fluorescence microscopy produces images that suggest the localization of CSN-CRL particles in autophagosomes. Our data place CSN-CRL in the category of large complexes that are degraded through autophagy.