Pellino proteins are molecules involved in various biological processes, particularly those related to the immune system. They regulate how the body responds to internal and external cues, participating in pathways that maintain cellular balance and respond to infections.
The Pellino Protein Family
The Pellino protein family in mammals consists of three distinct members: Pellino1, Pellino2, and Pellino3. These proteins share a similar structural blueprint, characterized by specific functional domains. Each Pellino protein possesses a C-terminal RING-like domain, essential for its E3 ubiquitin ligase activity.
Additionally, they feature an N-terminal hidden split Forkhead Associated (FHA) domain. This FHA domain is involved in interacting with other proteins, particularly those that have been phosphorylated. While they share these core structural elements, the specific cellular locations or expression patterns of Pellino1, Pellino2, and Pellino3 can vary, indicating their diverse roles within different biological pathways and cell types.
Key Biological Roles
Pellino proteins primarily function as E3 ubiquitin ligases, enzymes that attach ubiquitin, a small regulatory protein, to other proteins. This process, ubiquitination, acts like a molecular tag, determining a target protein’s fate, such as degradation, activation, or change in location. Pellino proteins can mediate different types of ubiquitination, including K11, K48, and K63-linked polyubiquitination.
Their activity is regulated by phosphorylation, where kinases like IRAK1 and IRAK4 add phosphate groups, activating their E3 ligase function. This activation is important for their involvement in cellular signaling pathways governing immune responses and inflammation. Pellino proteins participate in pathways initiated by pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and Interleukin-1 receptors (IL-1Rs), which detect microbial components and activate immune responses.
Pellino proteins are involved in the NF-κB signaling pathway, a central regulator of inflammation and immunity. Pellino1 can promote NF-κB activation by facilitating the ubiquitination of proteins like TRAF6 in the MyD88-dependent pathway or RIP1 in the TRIF-dependent pathway, both downstream of TLRs and IL-1Rs. They also influence the activation of mitogen-activated protein kinases (MAPKs) and interferon regulatory factors (IRFs), which produce inflammatory cytokines and interferons. For example, Pellino1’s E3 ligase activity can contribute to type I interferon expression. Specific interactions vary among family members; Pellino1 interacts with MyD88 and TBK1, while Pellino3 associates with NIK.
Pellino’s Influence on Health and Disease
Dysregulation of Pellino proteins can contribute to various health conditions, including autoimmune disorders, chronic inflammation, certain cancers, and responses to infections. They influence these conditions by modulating immune cell activity and inflammatory processes.
In autoimmune conditions, Pellino proteins can have complex roles. Pellino1, for example, inhibits noncanonical NF-κB activation and alleviates lupus-like disease in systemic lupus erythematosus by degrading NIK. However, in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, Pellino1’s role is debated. Some studies suggest it promotes disease progression by enhancing microglial activation, while others propose a protective role by inhibiting T-cell activation.
Pellino proteins are also implicated in chronic inflammatory diseases. In psoriasis, a common immune-mediated chronic inflammatory skin disease, Pellino1 is highly upregulated in skin lesions. Overexpression of Pellino1 promotes keratinocyte proliferation and triggers a pro-inflammatory state by activating immune cells and signaling pathways, including those involving IL-17-related cytokines. Targeting Pellino1 could help reduce the inflammatory signaling that drives psoriatic lesions.
In cancer, Pellino proteins can act as both promoters and suppressors of tumor development depending on the specific cancer type and family member. Pellino1 has been identified as a potential oncogene in certain cancers, including diffuse large B-cell lymphoma, breast cancer, and lung cancer, often by activating pathways that promote cell survival and growth. Specifically, Pellino1 can promote chemoresistance in lung cancer cells by stabilizing cIAP2, a protein that inhibits apoptosis. However, Pellino2 suppresses colorectal cancer progression by influencing the MAPK signaling pathway. Furthermore, Pellino1 levels are elevated in patients with colitis and colitis-associated colon cancer, where it contributes to macrophage-mediated inflammation and tumor development by targeting STAT3.
Pellino proteins are essential for detecting microbes and initiating innate and adaptive immune responses. For example, Pellino1 regulates the body’s response to respiratory viruses like rhinovirus and influenza A. While it generally promotes anti-inflammatory responses in isolated cells, its absence in the lung can paradoxically lead to increased inflammatory responses during viral infection. Similarly, Pellino1’s inhibition has been suggested to enhance bacterial clearance in lung infections like those caused by Haemophilus influenzae.