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Review
. 2023 Dec 18:14:1292022.
doi: 10.3389/fimmu.2023.1292022. eCollection 2023.

Biology of Pellino1: a potential therapeutic target for inflammation in diseases and cancers

Lili Yan  1 , Yueran Cui  1 , Juan Feng  1
Affiliations
Review

Biology of Pellino1: a potential therapeutic target for inflammation in diseases and cancers

Lili Yan et al. Front Immunol. .

Abstract

Pellino1 (Peli1) is a highly conserved E3 Ub ligase that exerts its biological functions by mediating target protein ubiquitination. Extensive evidence has demonstrated the crucial role of Peli1 in regulating inflammation by modulating various receptor signaling pathways, including interleukin-1 receptors, Toll-like receptors, nuclear factor-κB, mitogen-activated protein kinase, and phosphoinositide 3-kinase/AKT pathways. Peli1 has been implicated in the development of several diseases by influencing inflammation, apoptosis, necrosis, pyroptosis, autophagy, DNA damage repair, and glycolysis. Peli1 is a risk factor for most cancers, including breast cancer, lung cancer, and lymphoma. Conversely, Peli1 protects against herpes simplex virus infection, systemic lupus erythematosus, esophageal cancer, and toxic epidermolysis bullosa. Therefore, Peli1 is a potential therapeutic target that warrants further investigation. This comprehensive review summarizes the target proteins of Peli1, delineates their involvement in major signaling pathways and biological processes, explores their role in diseases, and discusses the potential clinical applications of Peli1-targeted therapy, highlighting the therapeutic prospects of Peli1 in various diseases.

Keywords: IL-1R/TLRs; NF-κB; Peli1; cancer; immune; inflammation; ubiquitination.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pellino1 in interleukin-1 receptors/Toll-like receptors, nuclear factor−κB, mitogen-activated protein kinase, and AKT pathways. Pellino1 (Peli1), activated by interleukin-1 receptor-associated kinase (IRAK) phosphorylation, promotes the degradation of tumor necrosis factor receptor-associated factor 3 (TRAF3) by mediating cellular inhibitor of apoptosis protein 2 (cIAP2) ubiquitination in the myeloid differentiation primary response protein 88 (MyD88)-dependent interleukin-1 receptors (IL-1R)/Toll-like receptors (TLRs) signaling pathway. This process facilitates the cytoplasmic translocation of IRAK1-IRAK-TRAF6-PELI1 (an intermediate complex). The transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) complex forms complex II (IRAK1-IRAK-TRAF6-PELI1-TAK1-TAB1-TAB2) in conjunction with an intermediate complex that subsequently assembles into TRAF6-TAK1-TAB1-TAB2 (complex III). TRAF6 mediates TAK1 complex ubiquitination and recruits the IkappaB kinase (IKK) complex via the K63/M1-UB Ub chain, ultimately activating nuclear factor−κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, and stimulating interferon regulatory factor 5 (IRF5) to induce interferon beta (IFN-β) production. In the Toll-interleukin-1 receptor-domain-containing adaptor-inducing IFN-beta (TRIF)-dependent Toll-like receptor (TLR)3/4 pathway, phosphorylated Peli1, in conjunction with the TBK1-Ikkϵ complex, mediates receptor-interacting protein kinase 1 (RIP1) ubiquitination, enabling RIP1 to recruit the IKK and TAK1 complexes through the K63/M1-UB Ub chain. This cascade activates NF-κB and MAPK signaling. The TBK1-Ikkϵ complex and Jun N-terminal kinase (JNK), activated by the TAK1 complex, can phosphorylate and activate IRF3, promoting IFN-β and Peli1 transcription. Peli1 enhances the positive feedback loop of IFN-β production. Peli1 promotes NF-κB canonical signaling by activating the IKK complex through TRAF6 and RIP1. NF-κB induces elevated miR-21 expression, inhibiting Peli1 expression, potentially forming a negative feedback loop. Peli1 mediates the ubiquitin-proteasome-dependent degradation of NIK, thus inhibiting NF-κB non-canonical signaling. However, Peli1 can also promote p100 to p52 processing and, ultimately, NF-κB non-canonical signaling by inhibiting TRAF3. Peli1 mediates ubiquitin-proteasome-dependent degradation of c-Rel. Peli1 activates the TAK1 complex via TRAF6 and RIP1, activating MAPK. Peli1 also inhibits TRAF3 via CIAP2, promoting JNK activation. Peli1 facilitates IRE1α phosphorylation by binding to HSP90, resulting in JNK activation. Peli1 inhibits phosphatase and tensin homolog (PTEN) by upregulating miR-44-3P, relieving Raf and phosphatidylinositol 3,4,5-trisphosphate (PIP3) repression, and ultimately activating extracellular signal-regulated kinase (ERK)1/2. In addition, Peli1 inhibits inducible co-stimulator (ICOS) through C-REL inhibition and activates phosphoinositide 3-kinase (PI3K), promoting PIP3 and AKT activation. Created using BioRender.com.
Figure 2
Figure 2
Peli1 regulation in cell death and autophagy. Upon tumor necrosis factor (TNF) stimulation, the TNFR1-associated death structural domain (TRADD) recruits cIAP1 and cIAP2 to RIPK1 via the TRAF2 and linear ubiquitin chain assembly complexes, forming complex I. Rapid ubiquitination of RIPK1 occurs. Complex I is deubiquitinated by A20 and cylindromatosis, forming complex II. Complex II bifurcates into complex IIa, triggering RIPK1-dependent apoptosis, and complex IIb, which induces necrosis. Complex I forms a TRADD-FADD-caspase-8 complex, leading to RIPK1-independent apoptosis. PELI1 preferentially recruits RIPK3 to form complex IIb by mediating RIPK1 ubiquitination in complex II. However, PELI1 mediates the ubiquitin-proteasome-dependent degradation of RIPK3, thereby inhibiting necrosis. PELI1 inhibits RIPK1-dependent or RIPK1-independent apoptosis by suppressing c-myc and promoting c-FLIP (a catalytically inactive caspase-8 homolog) expression. However, Peli1 can also promote apoptosis through tumor necrosis factor-related apoptosis-inducing ligand by upregulating IFN-β expression. Peli1 inhibits NF-κB non-classical signaling and downstream B-cell lymphoma-extra large via NIK, promoting apoptosis. Peli1 inhibits autophagy by mediating p62 ubiquitination, resulting in BIK accumulation, which activates downstream apoptotic signals. Peli1 inhibits lysosome formation and autophagic signaling by mediating the ubiquitin-proteasome-dependent degradation of lysosome-associated membrane protein 2. However, Peli1 can also promote autophagosome production by mediating the ubiquitination of K63-linked Beclin 1. In addition, Peli1 induces NLRP3 inflammasome production and pyroptosis through the ubiquitin-mediated modification of apoptosis-associated speck-like protein (ASC). Created using BioRender.com.
Figure 3
Figure 3
Peli1 in DNA damage repair. Upon ionizing radiation (IR) stimulation, PELI1 mediates nibrin (NBS1) ubiquitination and facilitates MRE11-RAD50-NBS1 (MRN) complex assembly, which is recruited to the DNA double-strand break (DSB) site by γH2AX and activated by ataxia-telangiectasia mutated (ATM) phosphorylation. The MRN complex enhances ATM phosphorylation, which mediates the phosphorylation of MDC1, thereby promoting the ubiquitination of histones by RNF8/RNF18 and establishing a platform for DNA damage repair. Peli1, recruited to the DSB site by γH2AX, promotes the nuclear export of murine double minute X (MDMX) by mediating MDMX ubiquitination, thus liberating P53 to activate the transcription of downstream genes in response to DNA damage repair. Peli1 binds to IRAK4 to promote IRAK1 recruitment and phosphorylation, which then translocates to the nucleus and co-localizes with γH2A, inhibiting the pro-apoptotic PIDDosome complex. Created using BioRender.com.
Figure 4
Figure 4
Peli1 in Tumors. Peli1 stabilizes SNAIL/SLUG via ubiquitination and the PI3K/AKT/GSK-3βpathway, contributing to breast and lung cancers EMT. Peli1 is detrimental to JQ1 drug tolerance in breast cancer through LSD1 degradation and the BRD4/LSD1/NuRD complex dissociation. Peli1 interacts with EGFR to promote breast cancer metastasis. Peli1 overexpression upregulates the expression of the apoptosis-inhibitory protein cIAP2, conferring resistance to cisplatin- and paclitaxel-induced apoptosis in lung cancers. Peli1 expression is upregulated in papillary thyroid carcinoma and promotes cancer cell proliferation and migration by activating the PI3K/AKT pathway. Elevated Peli1 expression induces lymphoma development by facilitating BCL6 ubiquitination and promoting the constitutive activation of the post-BCL6 B-cell signaling pathway. Peli1 is involved in palmitate-induced, TLR4-dependent lung metastasis in melanoma, whereas Peli1 inhibits melanoma progression through MDMX ubiquitination and cytoplasmic localization. Peli1 enhances the sensitivity of esophageal squamous carcinoma to radiotherapy by inhibiting the IR-induced activation of the non-canonical NF-κB pathway. Peli1 mediates PKCθubiquitination and inhibits glycolysis via TSC1 ubiquitination, negatively regulating antitumor activity in CD8+ T cells. In contrast, Peli1 exhibits positive antitumor capacity in macrophages by inhibiting glycolysis through IRAK1 TSC1 ubiquitination.Created using BioRender.com.
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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Outstanding Scientific Fund Q18 of the Shengjing Hospital (to JF) and the National Natural Science Foundation of China (No. 82271275 to JF).

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