Complement, complosome, and complotype: A perspective

Recent rapid progress in key technological advances, including the broader accessibility of single‐cell “omic” approaches, have allowed immunologists to gain important novel insights into the contributions of individual immune cells in protective immunity and immunopathologies. These insights also taught us that there is still much to uncover about the (cellular) networks underlying immune responses. For example, in the last decade, studies on a key component of innate immunity, the complement system, have defined intracellularly active complement (the complosome) as a key orchestrator of normal cell physiology. This added an unexpected facet to the biology of complement, which was long considered fully explored. Here, we will summarize succinctly the known activation modes and functions of the complosome and provide a perspective on the origins of intracellular complement. We will also make a case for extending assessments of the complotype, the individual inherited landscape of common variants in complement genes, to the complosome, and for reassessing patients with known serum complement deficiencies for complosome perturbations. Finally, we will discuss where we see current opportunities and hurdles for dissecting the compartmentalization of complement activities toward a better understanding of their contributions to cellular function in health and disease. Division of labor in the complement system: extracellular complement provides protection against bloodborne threats via target opsonization, inflammation induction, and pathogen killing (canonical functions). Intracellularly active complement, the complosome, evolved as a central orchestrator of basic physiological processes including control of cell metabolism, autophagy, vesicular transport, and gene transcription (noncanonical functions).