The roles of Pellino E3 ubiquitin ligases in immunity

Key Points

  • Toll-like receptors (TLRs) and NOD-like receptors (NLRs) sense pathogen-associated molecules and trigger effector pathways to facilitate the destruction and removal of the pathogen. Post-translational modifications, such as ubiquitylation, have important roles in regulating the activities and the levels of signalling molecules in these pathways.

  • The Pellino family (Pellino 1, Pellino 2 and Pellino 3) were initially identified as interleukin-1 receptor-associated kinase (IRAK)-interacting proteins with E3 ubiquitin ligase activity. They are activated by kinases such as IRAKs and TANK-binding kinase 1 (TBK1) and can promote ubiquitylation of their upstream kinases.

  • Pellino 1 regulates TIR domain-containing adaptor protein inducing IFNβ (TRIF)-dependent signalling in the TLR3 and TLR4 pathways by promoting the ubiquitylation of the kinase receptor-interacting protein 1 (RIP1) and the downstream activation of nuclear factor-κB (NF-κB), and by mediating the TRIF-dependent induction of type I interferons (IFNs). In addition, in microglial cells, Pellino 1 can mediate the myeloid differentiation primary-response protein 88 (MYD88)-dependent activation of mitogen-activated protein kinase (MAPK) pathways to trigger neuroinflammation.

  • Pellino 1 also functions as a negative regulator of T cell activation to ensure self tolerance is maintained and to avoid the development of autoimmunity.

  • Pellino 3 negatively regulates the TLR3-induced expression of type I IFNs by ubiquitylating TNF receptor-associated factor 6 (TRAF6) to inhibit the downstream activation of IFN-regulatory factor 7 (IRF7). In addition, Pellino 3 mediates nucleotide-binding oligomerization domain-containing protein 2 (NOD2) signalling and regulates intestinal inflammation by functioning as the E3 ubiquitin ligase for the RIP2 kinase.

  • Pellino 3 is cytoprotective in response to tumour necrosis factor (TNF) challenge, as it targets RIP1 and impairs the formation of the death-inducing signalling complex (DISC).

  • Further investigation of the role of Pellino proteins in immunity will provide a molecular and a functional understanding of their contribution to physiological and pathological conditions.


Pellino proteins were initially characterized as a family of E3 ubiquitin ligases that can catalyse the ubiquitylation of interleukin-1 receptor-associated kinase 1 (IRAK1) and regulate innate immune signalling pathways. More recently, physiological and molecular roles for members of the Pellino family have been described in the regulation of innate and adaptive immune responses by ubiquitylation. This Review describes the emerging roles of Pellino proteins in innate and adaptive immunity and discusses the mechanistic basis of these functions.

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Figure 1: Molecular features of Pellino proteins.
Figure 2: Pellino 1 regulates TLR signalling.
Figure 3: Pellino 1 negatively regulates T cell activation.
Figure 4: Roles of Pellino 3 in innate immune signalling.


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The work carried out in the author's laboratory related to this Review is supported by grants from Science Foundation Ireland (07/IN.1/B972 and 12/IA/1736) and the Health Research Board of Ireland (Grant No. PhD/2007/09).

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Correspondence to Paul N. Moynagh.

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Pattern recognition receptors

(PRRs). Host receptors (such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs)) that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane bound (for example, TLRs) or soluble cytoplasmic receptors (such as retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5) and NLRs).

Pathogen-associated molecular patterns

(PAMPs). Molecular motifs that are characteristic of bacteria and archaea and are recognized by the mammalian innate immune system.

Lys63-linked polyubiquitin chains

Polyubiquitin chains that are formed on a target protein linked through the lysine residue at position 63 (Lys63) in ubiquitin. In contrast to Lys48-linked polyubiquitin chains, which are the principal signal for targeting substrates for proteasomal degradation, Lys63-linked polyubiquitin modifications regulate protein function, target certain proteins for endocytosis, and/or facilitate the interaction of these proteins with other proteins that have specific ubiquitin-binding domains.

Chronic obstructive pulmonary disease

A group of diseases characterized by the pathological limitation of airflow in the airways, including chronic obstructive bronchitis and emphysema. These diseases are most often caused by tobacco smoking, but can also be caused by other airborne irritants, such as coal dust, and occasionally by genetic abnormalities, such as α1-antitrypsin deficiency.


The post-translational modification of proteins that involves the covalent attachment of a small ubiquitin-related modifier (SUMO) and that regulates the interactions of those proteins with other macromolecules.

Septic shock

A systemic response to severe bacterial infections, which are generally caused by Gram-negative bacterial endotoxins, that leads to a hyperactive and out-of-balance network of inflammatory cytokines, affecting vascular permeability, cardiac function and metabolic balance, and leading to tissue necrosis, multiple organ failure and death.

Polyinosinic–polycytidylic acid

(PolyI:C). A substance that is used as a mimic of viral double-stranded RNA, which is sensed by Toll-like receptor 3.

Self tolerance

Tolerance to an individual's own antigens that is achieved through both central and peripheral tolerance mechanisms, including T cell deletion, anergy and immune regulation.

Foam cells

Macrophages that localize to sites of early stage inflammation in the vessel wall and that subsequently ingest oxidized low-density lipoprotein and slowly become overloaded with lipids. They are called foam cells because of their appearance, including numerous cytoplasmic vesicles that contain cholesterol and other lipids. Foam cells eventually die and attract more macrophages, and further propagate the inflammation in the vessel wall.

Crohn's disease

One of two idiopathic inflammatory bowel diseases that are characterized by chronic intestinal inflammation. The inflammatory lesions of Crohn's disease can occur in any part of the gastrointestinal tract. By contrast, ulcerative colitis is typically confined to the colon and to the distal small bowel.

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Moynagh, P. The roles of Pellino E3 ubiquitin ligases in immunity. Nat Rev Immunol 14, 122–131 (2014).

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