Complement’s hidden arsenal: New insights and novel functions inside the cell

doi:10.1016/j.molimm.2017.01.004

Molecular Immunology

Volume 84, April 2017, Pages 2-9

https://doi.org/10.1016/j.molimm.2017.01.004 Get rights and content

Highlights

New studies have demonstrated major new intracellular roles for complement:

•
C3 is a damage-associated molecular pattern that can enhance intracellular innate immunity and help control cell survival.
•
A C3(H₂O) recycling pathway is a component of the intracellular complement system.
•
Autocrine activation of CD46 via T-cell derived C3b plays a key role in nutrient uptake and cellular metabolism.
•
C3 activation fragments and factor H act as chaperones for the processing of apoptotic cargo.
•
Intracellular C5 activation is essential for NLRP3 inflammasome assembly in CD4⁺ T cells.

The full importance and mechanisms of complement’s hidden intracellular arsenal continue to be elucidated. Other intracellular players including the C3a receptor (C3aR), the C5a receptor (C5aR), and factor B (FB) also are currently being evaluated. These new roles also suggest new therapeutic approaches.

Abstract

A key component of both innate and adaptive immunity, new understandings of the complement system are expanding its roles beyond that traditionally appreciated. Evidence is accumulating that complement has an intracellular arsenal of components that provide not only immune defense, but also assist in key interactions for host cell functions. Although early work has primarily centered on T cells, the intracellular complement system likely functions in many if not most cells of the body. Some of these functions may trace their origins to the primitive complement system that began as a primeval form of C3 likely tasked for protection from intracellular pathogen invasion. This later expanded to include extracellular defense as C3 became a secreted protein to patrol the vasculature. Other components were added to the growing system including regulators to protect host cells from the indiscriminate effects of this potent system. Contemporary cells may retain some of these vestigial remnants. We now know that a) C3 serves as a damage-associated molecular pattern (in particular by coating pathogens that translocate into cells), b) most cells store C3 and recycle C3(H₂O) for immediate use, and c) C3 assists in cellular survival and metabolic reprogramming. Other components also are part of this hidden arsenal including C5, properdin, factors H and B, and complement receptors. Importantly, better definition of the intracellular complement system may translate into new target discovery to assist in creating the next generation of complement therapeutics.

Introduction

The complement system traces its origins to more than a billion years ago when primitive proteins evolved to protect the cell from pathogens and to engage in intracellular metabolic processes. The complement system’s sophistication has grown enormously over the millennia yet has retained some of these ancient functions. An emerging concept is that the location of complement expression, in part, dictates its function [reviewed in (Kolev et al., 2014) and (Hess and Kemper, 2016)]. Thus, the role of complement’s intracellular arsenal may be just as important as its better known actions in the circulation.

This review focuses on expanding our view of complement pointing to major new intracellular roles. In this inner universe of interactions, C3 (among other components) has several newly recognized roles. These include being a damage-associated molecular pattern (DAMP) that can enhance intracellular innate immunity (Tam et al., 2014), a controller of cell survival (Liszewski et al., 2013) and a component of an extracellular/intracellular recycling pathway (Elvington et al., 2017). Further, autocrine activation of complement regulator CD46 (also known as membrane cofactor protein) via T-cell derived C3b plays a key role in nutrient uptake and enhances cellular metabolism essential for Th1 responses (Kolev et al., 2015). Additionally, C3 and factor H (FH) act as chaperones for the processing of apoptotic cargo (Baudino et al., 2014, Martin et al., 2016), while release of intracellular properdin and C3 stores in neutrophils may quickly instigate and enhance local complement activation against pathogens. More recently, intracellular C5 activation has been shown to be essential for NLRP3 inflammasome assembly in CD4⁺ T cells (Arbore et al., 2016), suggesting a critical link between these two components of innate immunity that determines effector responses. Thus, the full importance and mechanisms of complement’s hidden intracellular arsenal continue to be elucidated. Other intracellular players including the C3a receptor (C3aR), the C5a receptor (C5aR), and factor B (FB) also are currently being evaluated (Hess and Kemper, 2016).

Section snippets

The complement pathways

Our traditional understanding of complement traces its origins to about 125 years ago when the system was identified as a relatively unstable and heat-labile lytic substance in blood (plasma and serum) that “complemented” antibodies in lysing bacteria.

Since then, our knowledge of complement has grown immensely. We now know that the system consists of three major pathways of activation that ultimately result in the generation of a common lytic complex. Two target-specific initiating arms are the

Evolution-driven multi-tasking of complement

Evolutionary theory suggests that nature “preserves” its most vital components by multi-tasking them. This certainly applies to the complement system. C3- and FB-like proteins evolved at least a billion years ago to comprise the earliest complement system (Nonaka and Kimura, 2006, Pinto et al., 2007). While the evolutionary evidence for such complement gene function is fragmentary, a primeval form of C3 has been identified in the phylum Porifera (sponges) (Al-Sharif et al., 1998). Sponges are

New insights on the roles of intracellular C3

Recent studies have expanded our knowledge of C3 beyond that of the central component of the complement pathways that functions in the plasma and on host membranes.

A new appreciation is emerging for other roles of C3, especially from the vantage point of inside the cell. For example, while systemic and local complement activation were thought to occur primarily extracellularly, new studies demonstrate that protease-driven activation of C3 inside CD4⁺ T cells results in CD46 and C3a-mediated

Other intracellular components

The full scope of complement’s hidden intracellular arsenal continues to be discovered and defined. For example, polymorphonuclear neutrophils (PMN) contain intracellular stores of properdin (P) as well as C3 as a mechanism for their quick release into the local environment (Kouser et al., 2013b).

More recently, intracellular C5 activation has been shown to be necessary for NLRP3 inflammasome assembly in human CD4⁺ T cells, and this assembly is modulated by the differential activation of C5aR1

Conclusions

While we are only beginning to appreciate the exciting discovery of a seemingly ubiquitous and potent intracellular complement system arsenal, there are more questions than answers at present. In which cells does this intracellular system operate? What other pathways are engaged and for what reasons? What cell-specific mechanisms drive these events? How can this information be leveraged to create the next generation of complement therapeutics?

It is clear that new roles for intracellular

Disclosures

The authors have declared no conflicting financial interests exist.

Acknowledgements

Support was provided by the National Institutes of Health (R01 GM0099111 and R01 AI041592 to J.P.A.), the National Institutes of Health Training in the Immunobiology of Rheumatic Disease (2T32 AR007279, to M.E.) and the National Institutes of Health Training Grant in the Principles of Pulmonary Research (5T32 HL007317, to H.S.K.). Research reported in this publication is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of

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ReviewComplement’s hidden arsenal: New insights and novel functions inside the cell

Highlights

Abstract

Introduction

Section snippets

The complement pathways

Evolution-driven multi-tasking of complement

New insights on the roles of intracellular C3

Other intracellular components

Conclusions

Disclosures

Acknowledgements

Immunity

Immunobiology

Immunobiology

J. Biol. Chem.

Immunobiology

Immunity

Mol. Immunol.

Clin. Immunol.

Semin. Immunol.

Immunity

Cell

Immunity

Immunobiology

Kidney Int.

Semin. Immunol.

Semin. Immunol.

Blood

Int. J. Biochem. Cell Biol.

An evaluation of the role of properdin in alternative pathway activation on Neisseria meningitidis and Neisseria gonorrhoeae

J. Immunol.

Sea urchin coelomocytes specifically express a homologue of the complement component C3

J. Immunol.

T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells

Science

C3 opsonization regulates endocytic handling of apoptotic cells resulting in enhanced T-cell responses to cargo-derived antigens

Proc. Natl. Acad. Sci. U. S. A.

The making of a macromolecular machine: assembly of the membrane attack complex

Biochemistry

Complement regulator CD46 promotes immunoregulation by distinct effects on conventional and unconventional human T cells

Nat. Immunol.

The complement system in regulation of adaptive immunity

Nat. Immunol.

A C3(H2O) recycling pathway is a component of the intracellular complement system

J. Clin. Invest.

Review
Complement’s hidden arsenal: New insights and novel functions inside the cell

T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4⁺ T cells