Cleaving It All Behind: ADAMTS7 Degrades Factor H

Factor H (fH) is a soluble complement regulatory protein that limits complement amplification in the fluid phase and on cell surfaces. It accelerates the decay of the C3 convertases (i.e., C4b2b, C3bBb) and serves as a docking site (i.e., a cofactor) for factor I-mediated cleavage and inactivation of C3b into iC3b,¹ together preventing amplification of the cascade regardless of the initial activation pathway (e.g., classical, alternative, or lectin). Factor H binds to glycosaminoglycans and sialic acids, preferentially on mammalian host surfaces as opposed to pathogen surfaces, thereby limiting complement-initiated damage to self-cells while facilitating clearance of pathogens.¹ The molecular structure of fH includes 20 complement control protein (CCP) domains aligned linearly in a so-called “beads-on-a-string” configuration. CCPs 1–4 (N terminus) confer the complement regulatory functions, whereas CCPs 6–8 and 19–20 (C terminus) are involved in host cell binding.²

Paradigm shifting discoveries by multiple laboratories over the past two decades revealed that genetic mutations in fH and acquired autoantibodies reactive to fH that alter fH function are pathogenically linked to the development of atypical hemolytic uremic syndrome and, less frequently, to C3 glomerulopathy (C3G).³ Factors that regulate physiological or pathological degradation of this crucial complement regulator have not been previously described.

In the current issue of the JASN, Ma et al.⁴ use biochemical, immunological, and in vivo mouse models to convincingly demonstrate that ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7), a member of the disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) family, directly binds to fH CCPs 1–4 and cleaves fH at multiples sites within CCPs 1–7, thereby eliminating fH's complement regulatory ability. The investigators showed elevated serum levels of ADAMTS7 and reduced serum levels of fH in several murine, complement-dependent, kidney disease models of lupus and ischemia reperfusion injury and reported an inverse relationship between serum levels of ADAMTS7 and fH in humans with lupus nephritis. Levels of fH in mice genetically deficient in ADAMTS7 did not decline after induction of complement-mediated kidney diseases, the increased levels of fH associated with reduced disease severity. The protective effects of ADAMTS7 deletion were abolished when fH was silenced through adeno-associated virus encoding fH shRNA, providing a mechanistic link.

Together, the findings elucidate an unanticipated mechanism of controlling complement activation by regulating serum levels of fH. The results imply that ADAMTS7 could function physiologically to limit the amount of circulating, functional fH and thereby limit fH's ability to regulate complement. Under select conditions, increased production and release of ADAMTS7 augment fH cleavage, lowering serum fH levels, which thereby lifts restraint on complement activation to facilitate complement-mediated kidney injury.

Previous work by this group showed increased vascular smooth muscle cell (VSMC) production of ADAMTS7 after stimulation with H₂O₂ and proinflammatory cytokines, including TNF-α, IL-1β, and growth factor PDGF-BB.⁵ Intriguingly, many of these proinflammatory stimuli are upregulated in lupus nephritis (LN) among other inflammatory nephritides,^6,7 suggesting the testable hypothesis that increased inflammatory signaling indirectly amplifies complement activation by upregulating ADAMTS7-mediated fH degradation. While renal endothelium seems to represent a major source of ADAMTS7, single-cell transcriptional and proteomic analyses will be important to clearly define the various sources of this metalloprotease and to uncover how it is physiologically and pathologically regulated.

Genome‐wide association studies independently identified ADAMTS7 as a risk locus for coronary artery disease in humans.⁸ Functional studies showed that the risk allele is associated with increased levels of ADAMTS7 that increase neointima formation in balloon-injured rat arteries by stimulating VSMC migration through the degradation of cartilage oligomeric matrix protein.⁵ ADAMTS7 may also increase vascular injury through cleavage of thrombospondin-1 (TSP-1), resulting in bioactive TSP-1 fragments that would reduce endothelial cell migration and proliferation and thus impair vascular recovery.⁹ Whether the risk allele is specifically associated with LN and whether mechanistic links between ADAMTS7 and atherosclerosis involve fH cleavage need to be addressed.

As the enzymatic cleavage activity of ADAMTS7 likely involves multiple substrates and the regulators of ADAMTS7 expression are not well established, the clinical effects of ADAMTS7 inhibition are not yet predictable. Thus, while pharmacological targeting of ADAMTS7 to prevent atherosclerosis¹⁰ and to treat kidney disease in which the ADAMTS7/fH axis is implicated⁴ is of interest, careful monitoring for unanticipated side effects will be imperative. Meanwhile, testing available complement therapeutics¹¹ may be more prudent than inhibition of ADAMTS7, particularly for inflammatory kidney diseases.

In sum, the data presented by Ma et al.⁴ are important as they elucidate an unanticipated molecular mechanism of fH degradation, complement activation, and promotion of inflammatory kidney diseases. The findings pave the way for future studies aimed at understanding the source and the mechanisms that regulate ADAMTS7 production and how complement-associated and complement-independent effects of this metalloprotease are linked to inflammatory disease processes in general.

Disclosures

P.S. Heeger reports Consultancy: Mallinckrodt Pharmaceuticals and Vertex; Honoraria: Mallinckrodt and Vertex; and Advisory or Leadership Role: Mallinckrodt (paid scientific consultant), and Vertex (paid scientific consultant). P. Cravedi reports Consultancy: Calliditas Therapeutics and Chinook Therapeutics; Research Funding: Renal Research Institute; Honoraria: Advisor for Chinook Therapeutics; and Advisory or Leadership Role: Associate Editor for Journal of Nephrology and American Journal of Transplantation.

Funding

P.S. Heeger was supported by National Institute of Allergy and Infectious Diseases R01 AI141434, and P. Cravedi was supported by National Institute of Diabetes and Digestive Kidney Diseases R01 DK119431.

Author Contributions

P. Cravedi and P.S. Heeger wrote the original draft and reviewed and edited the manuscript.