Table 1. Ubiquitin modifying enzymes with allelic variants that have been associated with immunologic monogenic human syndromes.

Online Mendelian Inheritance in Man (OMIM) was queried for human E2s, E3s, and DUBs. Genes were included in the table above if the associated human monogenic syndrome resulted in autoinflammation, immunodeficiency, or lymphoproliferative defects. RING, Really Interesting New Gene. BTB, Broad-Complex, Tramtrack and Bric a brac. POZ, POxvirus and Zinc finger. SUMO, small ubiquitin-like (Ubl) modifier. HECT, Homologous to the E6-AP Carboxyl Terminus. OTU, ovarian tumor.

Gene	Alias	Class/Domain	Location	Human Phenotype	Molecular Phenotype
E2s
UBE2T	FANCT, HSPC150	E2	1q32.1	Fanconi anemia, complementation group T; pancytopenia [3]	UBE2T is an E2 that ubiquitinates FANCL and FANCD2; mutation leads to genome instability and bone marrow failure [3]
E3s
BIRC4	XIAP	RING E3 Ub ligase	Xq25	Lymphoproliferative syndrome, X-linked [4]	Restricts apoptosis through interactions with various caspases; mutation leads to increased susceptibility to apoptotic stimuli [4]
CBL	C-CBL, RNF55	RING E3 Ub ligase	11q23.3	Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia [5]	Ubiquitinates multiple receptor protein-tyrosine kinases; mutations lead to hyper-responsiveness to multiple cytokines and increased proliferation [5]
FANCL	POG	RING E3 Ub ligase	2p16.1	Fanconi anemia, complementation group L; pancytopenia [6]	FANCL monoubiquitinates FANCD2 in response to DNA damage; mutation leads to genome instability and bone marrow failure [6]
MIB1	DIP-1	RING E3 Ub ligase	18q11.2	Left-ventricular noncompaction 7 [7]	Reduced NOTCH 1 activity in peripheral blood leading to potential B and T cell defects [7,8]
RBCK1	HOIL-1, HOIL-1L	RBR E3 Ub ligase	20p13	Polyglucosan body myopathy 1 with or without immunodeficiency [9]	Defects in LUBAC lead to NFKB dysregulation, leading to both immunodeficiency and autoinflammation [9]
RNF31	HOIP	RBR E3 Ub ligase	14q12	Multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphanqiectasia [10]	Phenolype overlaps with HOIL1/RBCK1 mutated patients [10]
RAG1	RNF74	RING E3 Ub ligase	11 p12	Severe combined immunodeficiency, Omenn syndrome [11,12]	RAG1 is required for assembling mature antigen receptors on B & T lymphocytes; mutations in the RING domain impairs ubiquitin ligase activity and recombination [11,12]
RNF125	TRAC1	RING E3 Ub ligase	18q12.1	Tenorio syndrome [13]	Defects in RIG-I-IPS1-MDA5, interferon, PI3K-Akt signaling leading to a Sjögren-like syndrome [13]
RNF168		RING E3 Ub ligase	3q29	RIDDLE syndrome; immunodeficiency [14]	RNF168 is an E3 ubiquitin ligase critical for DNA double-strand break repair; mutations lead to defective DNA repair and immunodeficiency [14]
SLX4	BTB12	BTB/POZ domain; SUMO E3 ligase	16p13.3	Fanconi anemia, complementation group P; pancytopenia [15,16]	SLX4 interacts with SUMO-charged E2 UBC9 and functions as a SUMO E3 ligase; important for the local replicative DNA repair response [15,16]
TRAF3	LAP1, CAP1	RING E3 Ub ligase	14q32.32	Possible association with susceptibility to Herpes simplex vims (HSV) encephalitis [17]	Dominant-negative mutant TRAF3 impairs responsiveness to TLR3 agonists such as HSV [17]
ITCH	AIF4, AIP4, NAPP1	HECT E3 Ub ligase	20q 11.22	Autoimmune disease, multisystem, with facial dysmorphism [18]	Cooperates with A20 and CYLD to terminate NFKB signaling; implicated in multiple signaling pathways, mutations lead to immune dysrequlation [18, 19]
DUBS
TNFAIP3	A20	ZnF E3 Ub ligase; OTU domain, DUB	6q23_3	Autoinflammatory syndrome, familial, Behcet-like [20]	Mutations leading to truncated A20 increased NFKB activity due to defective removal of K634inked ubiquitin from RIPK1, NEMO, and TRAF6 [20]
OTULIN	AIPDS, FAM105B	OTU domain, DUB	5p15.2	Autoinflammation, panniculitis, and dermatosis syndrome [21]	OTULIN-deflcient patients have increased linear ubiquitination of ASC, NEMO, RIPK1. TNFR1, leading to severe inflammation [21]