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Review
. 2022 Feb 11;7(7):5615-5624.
doi: 10.1021/acsomega.1c06890. eCollection 2022 Feb 22.

A Comprehensive Review of Biological Roles and Interactions of Cullin-5 Protein

Iqra Bano  1 , Anum Sumera Soomro  2 , Syed Qamar Abbas  3 , Amirhossein Ahmadi  4 , Syed Shams Ul Hassan  5   6 , Tapan Behl  7 , Simona Bungau  8   9
Affiliations
Review

A Comprehensive Review of Biological Roles and Interactions of Cullin-5 Protein

Iqra Bano et al. ACS Omega. .

Erratum in

Abstract

Ubiquitination is a modification of proteins that has a powerful impact on protein function along with other cellular functions. This reaction is regulated through major enzymes, including E3 ligase as a chief enzyme. The Cullin-5 ubiquitin ligase (Cul5) possesses a variety of substrates that maintain the process of ubiquitination as well as proteasomal degradation. It regulates cell development, proliferation, and other physiological tasks in the human body. Moreover, it has been discovered that the expression of Cul5 plays a significant role in specific cancer cells while affecting the progression of tumor cells. This review is based on current knowledge about Cul5 and its expression, signaling pathways, regulation, virus-related responses, and inhibitors for therapeutic strategies.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Diagrammatic illustration of a few members of the CRL family and their specific functions within the cell, including the regulation of apoptosis, autophagy, DNA replication, the response against hypoxia, and viral infections. Each member has specific functions and is located in different parts of cells to maintain homeostasis by protein–protein interactions.
Figure 2
Figure 2
Diagrammatic illustration of various functions of Cul5, including its involvement in brain injury, miR-145, aqua protein regulation, granulocyte differentiation, tumor formation, and cell cycle progression.
Figure 3
Figure 3
A schematic diagram of Cul5 ubiquitin ligase function and the interaction with proteins, illustrating the Cul5 complex that includes the ubiquitin, Rbx2, elongin B/C complexes, and SOCS box proteins. Ubiquitin (Ub) is initially activated in an ATP-dependent event that creates a thioester intermediate, which includes the carboxy-terminal glycine region of ubiquitin and the active site cysteine sequence on the ubiquitin-activating enzyme E1. Afterward, ubiquitin is transported to the cysteine active site of ubiquitin-conjugating enzyme E2. When using RING-finger E3s, ubiquitin is directly transported from E2 to the target molecule. Afterward, the ubiquitin chain substrate is recognized and degraded via the proteasome. Cul5 may assemble with the RING subunit RBX2 in the CRL5 family. RBX2 is necessary for the direct binding of NEDD8 to either lysine residue of Cul5. The CRL5 is activated once Cul5 is post-translationally changed by NEDD8 (neddylation). Meanwhile, the deneddylation through the COP9 signalosome (CSN) removes NEDD8 from CUL5 and thus inactivates it.
Figure 4
Figure 4
Schematic representation of targeting Cul5 for anticancer drug discovery. Cul5 has many specific substrates like DEPTOR, TRIAD1, NOXA, SOCS, and HSP90. Therefore, novel inhibitors can be discovered by targeting specific pathways involving these substrates and their linkage to tumorigenesis.
Figure 5
Figure 5
Representation of human cancers associated with the Cul5 protein, including breast cancer, gastric cancer, colon cancer, thyroid cancer, liver cancer, prostate cancer, lung cancer, ovarian cancer, and renal cancer.
Figure 6
Figure 6
Importance of Cul5 and SOCS3-mediated integrin 1 turnover in regulating SCLC metastasis. The lack of Cul5 and SOCS3 prevented integrin 1 from degrading, which stabilized integrin 1 and triggered downstream FA/Src signaling that ultimately led to SCLC metastasis. Dasatinib, a FDA-approved Src inhibitor, is effective against SCLCs that lack Cul5. This shows that Cul5 and SOCS3 have therapeutic implications.
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