COP9 signalosome subunit 8 is essential for peripheral T cell homeostasis and antigen receptor–induced entry into the cell cycle from quiescence

Abstract

Engagement of antigen receptors triggers the proliferation and functional activation of lymphocytes. Here we report that T cell homeostasis and antigen-induced responses require the COP9 signalosome (CSN), a regulator of the ubiquitin-proteasome system. Conditional deletion of the CSN subunit Csn8 in peripheral T lymphocytes disrupted formation of the CSN complex, reduced T cell survival and proliferation in vivo and impaired antigen-induced production of interleukin 2. Moreover, Csn8-deficient T cells showed defective entry into the cell cycle from the G0 quiescent state. This phenotype was associated with a lack of signal-induced expression of cell cycle-related genes, including G1 cyclins and cyclin-dependent kinases, and with excessive induction of p21(Cip1). Our data define a CSN-dependent pathway of transcriptional control that is essential for antigen-induced initiation of T cell proliferation.

The Organization of a CSN5-containing Subcomplex of the COP9 Signalosome

“…These interactions then conceivably leave the C-terminal half of CSN4 (amino acids 235-395) available for interaction with extra-complex proteins. In this vein, this end of CSN4 would be similar to the distal regions of the CSN7 tail, which bind a variety of proteins such as RNR2 and PCIP1 (40), and the non-PCI region of CSN1, which has transcriptional transactivation activity (41). The C-terminal half of CSN6 is required for its interaction with both CSN4 and CSN7, leaving its MPN domain available for interaction with CSN5.…”

COP9 Signalosome Subunit Csn8 Is Involved in Maintaining Proper Duration of the G1 Phase

“…These observations indicate that Csn8 has an important role in maintaining the structural integrity of the complex despite its peripheral position in the complex (16). Germline deletion of Csn8, like germline deletion of other CSN genes in mouse, caused early embryonic lethality (4). Restricted deletion of Csn8 in peripheral T cells abolished the ability of the quiescent cells to enter the cell cycle in response to stimulation, but in cycling T-cells, Csn8 was not required for continued cell division (4).…”

“…Gene targeting studies in mice showed that CSN is involved in diverse developmental and physiological processes including but not limited to embryonic development, immune responses, cell cycle control, and cardiovascular functions (3)(4)(5)(6)(7)(8)(9). At the molecular level, CSN has been best characterized as a regulator of cullin-RING family of ubiquitin E3 ligases (CRLs).…”

Fungal development and the COP9 signalosome

“…In addition, plant CSN is required for the survival of seedlings and is involved in pathogen response [2]. In mice and flies, the absence of CSN causes embryonic death, whereas aberrant expression has been associated with tumour growth [5][6][7]. CSN is a platform for associated proteins and plays a central role in regulating post-translational processes as protein ubiquitination/deubiquitination, neddylation/deneddylation and phosphorylation.…”