Mechanisms That Regulate Peripheral Immune Responses to Control Organ-Specific Autoimmunity

Table 1

E3 Ligases that play an important role in preventing autoimmunity.

Name	References	Type of E3 ligase	Function
Cbl-b	[40–45]	RING type	Ubiquitinates PLC-γ1 and PKC-θ downstream of TCR signalling. Also binds to and ubiquitinates P85 subunit of PI3K to inhibit CD28-mediated triggering of PI3K. Critical role in T-cell anergy.
Itch	[46–50]	HECT type	Important role in Th cell differentiation. Binds to a number of substrates including Notch, c-Flip, Smad2, p63, and p73. Ubiquitinates Bcl-10, JunB, Cbl-b, and PKC-θ and targets them for degradation. Binds to and is regulated by the E3 ligase Ndfip1.
Nedd4	[51]	HECT type	Binds to and ubiquitinates a number of targets that targets them for degradation including JunB, Cbl-b, c-Cbl, Notch, PTEN, PLC-γ1, and Bcl-10.
Ndfip1	[52–54]	HECT type	Associates with Nedd4 and is a negative regulator of Itch. Other targets include p63, p73, and c-Flip.
Grail	[55–57]	RING type	Selectively inhibits RhoGTPase activity but does not affect the Ras/MAPK kinase pathway. Inhibits IL-2 production and T-cell proliferation.
Traf6	[26, 58]	RING type	Binds to and ubiquitinates NEMO targeting it for degradation. Leads to upregulation of NF-κB signalling in response to TCR signaling.
Roquin	[59–61]	RING type	Binds to RNA-protein complexes and targets themfor degradation. Important role in posttranscriptional regulation of target gene expression. Targets include ICOS, CXCR5, PDCD1, CCL5, Il21, and CD100.