Ubiquitin-specific protease: an emerging key player in cardiomyopathy

Abstract

Protein quality control (PQC) plays a vital role in maintaining normal heart function, as cardiomyocytes are relatively sensitive to misfolded or damaged proteins, which tend to accumulate under pathological conditions. Ubiquitin-specific protease (USP) is the largest deubiquitinating enzyme family and a key component of the ubiquitin proteasome system (UPS), which is a non-lysosomal protein degradation machinery to mediate PQC in cells. USPs regulate the stability or activity of the target proteins that involve intracellular signaling, transcriptional control of inflammation, antioxidation, and cell growth. Recent studies demonstrate that the USPs can regulate fibrosis, lipid metabolism, glucose homeostasis, hypertrophic response, post-ischemic recovery and cell death such as apoptosis and ferroptosis in cardiomyocytes. Since myocardial cell loss is an important component of cardiomyopathy, therefore, these findings suggest that the UPSs play emerging roles in cardiomyopathy. This review briefly summarizes recent literature on the regulatory roles of USPs in the occurrence and development of cardiomyopathy, giving us new insights into the molecular mechanisms of USPs in different cardiomyopathy and potential preventive strategies for cardiomyopathy.

Keywords: Cardiomyopathy; Deubiquitination; PQC; USP.

Fig. 1

USPs and NF-κB signaling pathway. NF-κB signaling is activated via canonical or noncanonical pathway. A The canonical pathway is activated by stimulation of TLRs and TNFRs. TLRs recruits MyD88 to form a complex with IRAK1 and IRAK4. Then IRAK1 interacts with E3 ligase TRAF6. TRAF6 functions with E2 enzymes to promote K63-linked polyubiquitination of target proteins, including TRAF6 itself. Ubiquitinated TRAF6 subsequently recruits TAK1 and TABs, which then activates the IKK complex. IKK complex phosphorylates the inhibitory NF-κB subunit IκB, leading to IκB ubiquitination through the SCFβTrCP ligase-dependent proteasome degradation. As a result, NF-κB members NF-κB1 (also named p50), RelA (also named p65), and c-Rel are released and translocated from the cytoplasm to the nucleus for DNA binding and regulation of downstream gene expression. While TNFRs recruit the E3 ligases c-IAP1 and c-IAP2 to promote Lys63 polyubiquitylation of RIP1 and themselves to form a platform with TRAF2/5. This platform interacts with TAK1-TABs complex for further NF-κB activation. Thus, the TAK1-TABs complex is critical for TLRs and TNFRs mediated NF-κB canonical signaling activation. B The noncanonical pathways is mainly dependent on the activation of NF-κB2 (p100)/ RelB complex, which specifically responds to TNFRs receptors such as BAFF and CD40 and recruitment of TRAF2 and TRAF3. The receptor complex interacts with TBK1 and phosphorylates NIK. Ikkα is activated by NIK to phosphorylates p100. Then, p100 is processed to its active form, p52 and translates to the nucleus with RelB for target genes expression. Different USPs mediate deubiquitylations in the process of NF-κB canonical and noncanonical pathways. NF-κB, Nuclear factor-κB; TLRs, Toll-like receptors; TNFRs, tumor Necrosis Factor Receptors; IRAK1/4, Interleukin-1 receptor-associated kinase1/4; TRAF2/3/5/6; TNFR-associated factor 2/3/5/6; TAK1, TGFβ-activated kinase 1; TAB, TAK1-binding protein; TRADD, TNFR1-associated DEATH domain protein; c-IAP1/2, cellular inhibitor of apoptosis 1/2; RIPK1, receptor-interacting protein kinase 1; IKK, NF-κB (IκB) kinase; NIK, NF-κB-inducing kinase; TBK1, TANK-binding kinase 1; BAFF, B-cell activating factor belonging to TNF family; SCFβTRCP, Skp–cullin–F-box–βTRCP; CYLD, cylindromatosis; OTUB1, OTU Deubiquitinase, Ubiquitin Aldehyde Binding 1; USP4/7, Ubiquitin-specific protease 4/7; Ub, ubiquitin; P, phosphorylation

Fig. 2

USPs and TGF-β signaling pathway. The TGF-β signaling pathway is activated via the binding of TGF-β ligands to TGF-β type II receptors (TβRII). After the binding of TβRII, TβRI is recruited to form a functional heterologous complex and is activated as TβRI kinase by TβRII, which transphosphorylases the glutamine synthetase domain of TβRI. Activated TβRI phosphorylates and activates Smad2 and Smad3 (Smad2/3). Activated Smad2/3 interacts with Smad4 to produce an activation complex, which then translocate into nucleus to control the transcription of target genes. Smad7, an I-Smad, blocks the phosphorylation and activation of Smad2/3 by competing with the binding to TβRI. Smad7 also binds to Smurf2 to form an E3 ubiquitin ligase, causing the degradation of receptors. Smurf1 and ALK5 function as competitive with Smurf2 and enhance the turnover of receptors. In addition, TRAF6 and TAK1 facilitate the activation of p38 /MAPK and JNK, resulting in the control of cell growth and proliferation. Different USPs mediate deubiquitinations in the process of TGF-β canonical and noncanonical pathways. TGF-β, transforming growth factor beta; TβRI/II, TGF-β type I/II receptors; SMAD2/3/4, small mothers against decapentaplegic 2/3/4; TRAF6, tumor necrosis factor receptor-associated factor 6; TAK1, TGF-β-activated kinase 1; JNK, c-Jun N-terminal kinase; Smurf1/2, Smad ubiquitin regulatory factor 1/2; ALK5, activin receptor-like kinase 5; I-Smad, inhibitory Smad; CYLD, cylindromatosis; USP4/9X, Ubiquitin-specific protease 4/9X; Ub, ubiquitin; P, phosphorylation

Fig. 3

USPs and Nrf2 signaling pathway. The key components of the Nrf2 pathway are Nrf2, Keap1 and CUL3 scaffold protein (with Rbx1). CUL3 and Keap1 form dimers for the E3 ubiquitin ligase complex, which binds to one Nrf2 with two binding motifs (DLG and ETGE) and degrades Nrf2 protein. Phosphorylation of p62 remarkedly increases the binding affinity of P62 with Keap1, leading the separation of Nrf2 from Keap1 and accumulation of cytoplasmic Nrf2. Nrf2 is then translocated into nucleus and targets ARE genes. Nrf2, Nuclear factor erythro2-related factor 2 (NFE2L2); Keap1, Kelch-like ECH-associating protein 1; CUL3, Cullin 3; Rbx1, Ring box protein 1; ARE, antioxidant response element; USP, Ubiquitin-specific protease; Ub, ubiquitin; P, phosphorylation

Fig. 4

USPs and p53 signaling pathway. p53 forms tetramers and translocate into nucleus, where p53 binds and activates target genes transcription to regulate many different biological processes in response to cellular stress. p53 protein keeps at a very level under normal condition, it is tightly regulated by MDM2, which promotes ubiquitination and proteasome-dependent degradation of p53. p53 itself binds to MDM2 to form a feedback loop. ARF binds to MDM2, leading to the rapid degradation of MDM2 and accumulation of p53. p53 proteins and p53 transcriptional activators HIF-1α can be ubiquitinated and proteasomal degraded in normal condition, whereas it is oppositely regulated by DUBs in stress condition. ARF, alternate open reading frame; MDM2, Mouse double minute 2; HIF-1α, hypoxia inducible factor-1α; RBM28, RNA-binding protein; CYLD, cylindromatosis; USP, Ubiquitin-specific protease; Ub, ubiquitin; P, phosphorylation

Fig. 5

USPs and cardiomyopathies. The USPs regulate several signaling pathways in cardiomyopathies. Propelled by these signaling pathways, the cardiomyocytes gradually undergo oxidative stress and chronic inflammation and abnormal metabolism, leading to the pathological processes of heart hypertrophy, fibrosis, apoptosis, and cell death, resulting in cardiac dysfunction and advancing the development of cardiomyopathies