TABLE 7.

Representative ubiquitination events in health and diseases.

Diseases and biological processes		Protein substrates	Effects
Aging		TBK1	K63 polyubiquitination of TBK1 promotes TBK1 phosphorylation to enhance mitophagy and attenuate cardiac aging. 864
		daf‐16	The Ub ligase RLE‐1 selectively poly‐ubiquitinates daf‐16 and promotes proteasomal degradation. Inhibition of RLE‐1 prolongs lifespan in C. elegans. 865
		BMAL1	STUB1 ubiquitinates and degrades the substrate BMAL1, attenuating hydrogen peroxide‐induced cellular senescence. 938
Immune regulation	Viral infection	IRF7	NEURL3 promotes innate antiviral responses by catalyzing K63‐linked poly‐ubiquitination of IRF7 at K375. 872
	Viral infection	RIG‐I	The CoV nucleocapsid (N) protein of SADS‐CoV interacts with RIG‐I and promotes its K27‐, K48‐, and K63‐linked ubiquitination to induce RIG‐I degradation, which further inhibits the host IFN‐β response. 879
	Viral infection	RIG‐I	lncRNAs can promote influenza A virus (IAV) replication and immune evasion by restricting RIG‐I K63 ubiquitination mediated by TRIM25. 880
	Viral infection	PPE	Mycobacterial PPE protein ubiquitination mediated by MKRN1 suppresses the innate immune response. 881
	Viral infection	MAVS	Viral infection enhances the interaction between USP18 and MAVS and promotes the K63‐linked ubiquitination of MAVS to upregulate the production of IFN‐I. 882 RNF115 interacts with MAVS to promote K48 ubiquitination of MAVS, and loss of RNF115 enhances antiviral signaling triggered by RNA viruses. 883
	Autoimmune disease	c‐Rel	Peli1 negatively regulates T cell activation and inhibit the development of autoimmunity through K48 ubiquitination dependent degradation of c‐Rel. 875
Metabolic disorders	Insulin resistance	MG53	MG53 acts as an E3 ligase targeting insulin receptor and IRS1 for Ub‐dependent degradation. Overexpression of MG53 is sufficient to induce muscle insulin resistance and metabolic syndrome. 887
	Diabetes	EZH2	Suppressive role of E3 Ub ligase FBW7 in type I diabetes in nonobese diabetic mice through mediation of ubiquitination of EZH2. 886
Cancers	Multiple cancers	p53	The tumor suppressor p53 is degraded by ubiquitination mediated by MDM2, resulting in immortal cancer cell proliferation. 895
	Liver cancer	Smad4	USP10 stabilizes Smad4 by ubiquitinating it, activates TGF‐β signaling, and promotes liver cancer metastasis. 900
	PC	TRAF6	USP4 is highly expressed in PC. It stabilizes TRAF6 and activates the NF‐κB signaling pathway to enhance the proliferation, migration and invasion of PC cells. 902
	Ovarian cancer	BCL6	USP14 expression is increased in cisplatin‐resistant ovarian cancer cells. It inhibits ovarian cancer cell apoptosis by stabilizing BCL6, which increases ovarian cancer cisplatin resistance. 904
	PDAC	DRYK1A	USP22 is highly expressed in PDAC. It enhances the growth and colony formation ability of cancer cells by regulating DRYK1A. 905
	Gastric cancer	SMAD2	USP32 is highly expressed in gastric cancer and is closely related to the stage and prognosis of gastric cancer patients. Downregulation of USP32 significantly reduces SMAD2 expression, thereby inhibiting the proliferation, migration, and resistance to cisplatin of gastric cancer cells. 906
	Liver cancer	TBLR1	USP1 promotes the survival of liver circulating tumor cells in the bloodstream by deubiquitinating and stabilizing TBLR1. 907
	Liver cancer	RAB1A	USP2a is highly expressed in HCC tissues and is positively correlated with poor prognosis. USP2a can deubiquitinate and stabilize RAB1A to promote HCC progression. 908
	Multiple cancers	K‐Ras	Ubiquitination of K‐Ras can enhance its interaction with PI3K, leading to abnormal activation of the PI3K/AKT signaling pathway. This is one of the mechanisms by which the G12V mutation of K‐Ras causes malignant cell proliferation. 909
CVDs	Cardiac fibrosis	RIP1	Peli1 silencing abrogates mechanical stretch‐induced polyubiquitination of TRAF6 and RIP1 and consequently decreases the DNA binding activity of NF‐κB in neonatal rat cardiac fibroblasts. 913
	Vascular lesions	HIF	The loss‐of‐function mutation of VHL can inhibit the normal degradation of its downstream substrate HIF. Accumulated HIF activates downstream target genes such as VEGF, leading to the formation of vascular lesions. 939
Neurodegenerative diseases	AD	C/EBPβ	Peli1 can directly ubiquitinate and degrade C/EBPβ, inhibits the phagocytosis of microglial cells, thus slowing down Aβ clearance in the brain of AD mice. 929
	AD	C/EBPβ	Loss of COP1 results in rapid accumulation of the transcription factor C/EBPβ, which drives the expression of proinflammatory and neurodegeneration‐related genes and accelerates the neurodegeneration of AD. 928
	AD	TAp73	Aβ42 can lead to hyperphosphorylation of Itch by abnormally activating the JNK signaling pathway. Hyperphosphorylated Itch ubiquitinates and degrades TAp73, leading to abnormal expression of important neuronal cyclins and causing neuronal apoptosis, which accelerates AD progression. 926
	AD	ESR2	The HECT family protein E6AP can activate the transcription of ESR2, which reduces Aβ deposition in the hippocampus and improves learning and memory in AD rats. 927
	PD	Synphilin 1	The UbcH7‐parkin complex promotes the ubiquitination and degradation of several proteins via the 26S proteasome. Cellular accumulation of the UbcH7‐parkin targets, α‐synuclein and synphilin‐1, has been associated with PD. 940
	ALS	TDP‐43	The occurrence of ALS is related to neuronal cell death caused by the abnormal aggregation of highly phosphorylated and ubiquitinated pathological TDP‐43. 941 Insufficient degradation of abnormally aggregated TDP‐43 protein leads to cell death and inflammation, which is one of the important mechanisms in the pathogenesis of ALS. 935

Abbreviations: AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; PC, pancreatic cancer; PDAC, pancreatic ductal adenocarcinoma; PD, Parkinson's disease.