Review
The COP9 signalosome: more than a protease

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The COP9 signalosome (CSN) is a conserved protein complex that functions in the ubiquitin–proteasome pathway. After two decades of research, we now know that the CSN is a multi-subunit protease that regulates the activity of cullin–RING ligase (CRL) families of ubiquitin E3 complexes. The CSN is rapidly emerging as a key player in the DNA-damage response, cell-cycle control and gene expression. The independent functions of CSN5 (also known as JAB1) add to the complexity of the CSN machinery. Here, we provide an updated view of the structure, functions and regulation of this protein complex.

Section snippets

The COP9 signalosome: a brief historical remark

The COP9 signalosome (CSN) is a conserved protein complex, typically consisting of eight subunits designated CSN1–CSN8 (Table 1). The CSN was originally identified in plants, based on a group of mutants exhibiting constitutive photomorphogenesis, pigmented seed-coats and premature death [1]. Later, inactivation of CSN genes was shown to cause profound detriments in many other organisms (Table 2). The discovery that the CSN contains Nedd8 (see Glossary) isopeptidase activity [2] immediately

Structural features and architecture

An archetypical CSN comprises eight subunits: six subunits with a PCI (also known as PINT) domain and two subunits with an MPN domain [3] (Table 1). Exceptions to this otherwise general paradigm can be found in yeast. The fission yeast Schizosaccharomyces pombe possesses a smaller version of the CSN, consisting only of six subunits rather than eight [4], whereas a more distant CSN-like complex has been described in the budding yeast Saccharomyces cerevisiae [3]. The PCI and MPN domains are also

The CSN holocomplex and subcomplexes

Most CSN subunits (except for CSN5; see later) are more stable in vivo as part of the holocomplex compared with their monomeric form. Studies with null mutants from Aspergillus nidulans, plants and vertebrate animals indicate that the loss of one subunit leads to loss of the entire complex 16, 18. As a result, A. thaliana null mutants for each of the CSN subunits exhibit nearly identical seedling lethal phenotypes and each germline CSN gene knockout in mouse causes early embryonic lethality (

The CSN as a cullin deneddylase

The best characterized biochemical activity that can be ascribed directly to the CSN is the isopeptidase activity that removes a Nedd8 (or Rub1) modification from the cullin subunit of CRL ubiquitin ligase complexes 2, 27, 28 (Box 1, Figure I). Nedd8 conjugation and removal, termed neddylation and deneddylation, respectively, represent an important mechanism by which CRL activity is regulated. For comprehensive reviews on this largest class of ubiquitin E3 ligases, see Refs 29, 30.

CSN-mediated

CSN5: a multifunctional subunit in multiple complexes

Among the eight CSN subunits, CSN5 is unique; not only does it harbor the catalytic center of the CSN isopeptidase activity, it can also stably exist independently of the CSN in vivo [3]. Reducing cellular CSN5 levels depletes monomeric CSN5 much more dramatically than the CSN holocomplex 22, 23, 34, 35, 36. Similarly, transient CSN5 overexpression in cultured cells usually causes an increase in CSN5 monomers with little effect on CSN holocomplex levels [37]. Although early reports did not

The CSN cellular functions

The CSN is involved in diverse cellular processes. Here, we focus on the aspects in which substantial progress has been made in advancing an understanding of the complex.

How is the CSN regulated?

As a potent protease that can act on all neddylated cullins, cellular CSN activity must be tightly regulated. The CSN can selectively deneddylate specific CRLs through differential protein interactions. For example, UV irradiation can trigger the rapid release of the CSN from the Cul4–DDB1DDB2 complex, leading to its transient hyperneddylation [69]. Simultaneously, UV irradiation induces the association of the CSN with the chromatin-bound Cul4–DDB1CSA complex which, interestingly, is recruited

Concluding remarks

The progress in delineating the specific roles of the CSN during various cellular processes also raises outstanding questions concerning CSN functions and mechanisms. Recent CSN knockout studies show that, as expected, a CSN deficiency causes cullin hyperneddylation. Perplexingly, several CRL substrates (e.g. p27, Pdcd4 and IκB-α) can still undergo signal-dependent degradation normally despite the loss of the CSN and its deneddylation activity 49, 68, 75. The disagreement between CRL

Acknowledgements

The authors would like to apologize for not being able to cite many important studies on CSN and Nedd8 owing to space limitations.

Glossary

9–1–1 complex
Rad9–Rad1–Hus1 complex. A heterotrimeric protein complex that forms a ‘doughnut-shaped’ sliding clamp around DNA after damage and/or replication fork stalling.
CAND1
cullin-associated and neddylation-dissociated 1. This protein specifically associates with deneddylated cullins to sequester them in an unassembled and inactive state. It was previously named TBP-interacting protein 120A (TIP120A).
CRLs
cullin–RING ligases, a superfamily of ubiquitin ligases. It typically consists of a

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