GRAIL (gene related to anergy in lymphocytes) regulates cytoskeletal reorganization through ubiquitination and degradation of Arp2/3 subunit 5 and coronin 1A.
Anergy is an important mechanism for the maintenance of peripheral tolerance and avoidance of autoimmunity. The up-regulation of E3 ubiqitin ligases, including GRAIL (gene related to anergy in lymphocytes), is a key event in the induction and preservation of anergy in T cells. However, the mechanisms of GRAIL-mediated anergy induction are still not completely understood. We examined which proteins serve as substrates for GRAIL in anergic T cells. Arp2/3-5 (actin-related protein 2/3 subunit 5) and coronin 1A were polyubiquitinated by GRAIL via Lys-48 and Lys-63 linkages. In anergic T cells and GRAIL-overexpressed T cells, the expression of Arp2/3-5 and coronin 1A was reduced. Furthermore, we demonstrated that GRAIL impaired lamellipodium formation and reduced the accumulation of F-actin at the immunological synapse. GRAIL functions via the ubiquitination and degradation of actin cytoskeleton-associated proteins, in particular Arp2/3-5 and coronin 1A. These data reveal that GRAIL regulates proteins involved in the actin cytoskeletal organization, thereby maintaining the unresponsive state of anergic T cells.
Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
Daiju
D
Ichikawa
Miho
M
Mizuno
Takashi
T
Yamamura
Sachiko
S
Miyake
D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D008840:Microfilament Proteins; C072061:coronin proteins; D015759:Ionomycin; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases