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A Molecular Concept of the Properdin Pathway (Complement Activation/Initiating Factor/Properdin Activation/Properdin Receptor/Multisubunit Enzymes) RUDOLF G

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A Molecular Concept of the Properdin Pathway (Complement Activation/Initiating Factor/Properdin Activation/Properdin Receptor/Multisubunit Enzymes) RUDOLF G Proc. Nat. Acad. Sci. USA Vol. 73, No. 2, pp. 612-616, February 1976 Immunology A molecular concept of the properdin pathway (complement activation/initiating factor/properdin activation/properdin receptor/multisubunit enzymes) RUDOLF G. MEDICUS, ROBERT D. SCHREIBER, OTTO GOTZE, AND HANS J. MJLLER-EBERHARD Department of Molecular Immunology, Scripps Clinic and Research Foundation, La Jolla, California 92037 Contributed by Hans J. Mitler-Eberhard, November 14,1975 ABSTRACT The sequential events of the properdin sys- mation of the properdin-dependent convertase which cata- tem were analyzed. Properdin-depleted serum allows the for- lyzes opsonization and activation of the membrane attack mation of a Factor B- and D-dependent C3 convertase. This enzyme, called the properdin-receptor-forming enzyme, was system. shown to utilize a novel serum component, the initiating fac- Initiation of the properdin pathway without tor. The protein is a a-globulin in recursor form and is dis- properdin (P) tinct from immunoglobulins. The function of the enzyme is to deposit C3b on the surface of activator particles. Appar- In exploring the possible role of P in the initiation of the ently doublets of C3b are required for the formation of the pathway, serum was immunochemically depleted of P. In properdin-activating principle. It consists of a complex con- addition, to block the classical pathway, C4 was removed taining surface-bound C3b and activated Factor B. Properdin precursor is activated by binding to this complex without de- from the same serum. Treatment of the depleted serum with tectable change in molecular weight. The transition of pro- yeast cell walls (zymosan) resulted in uptake of C3 by the perdin precursor to activated properdin is probably caused particles. This uptake was dependent upon the presence of by a conformational change. The complex, consisting of Factors B and D and magnesium ions and, as will be de- bound C3b, properdin, and activated Factor B, represents the scribed below, on Factor I (Table 1). Treatment for 60 min enzyme that acts on C5, thereby initiating self-assembly of at 370 caused 15-22% consumption of serum C3. In absence the membrane attack system. Native C3 is not needed for the function of the enzyme. It is disassembled by soluble C3 or of zymosan, B, or D, CS consumption did not exceed 7%. C3b and its formation is under the control of the properdin- This finding pointed out the existence of a C3 convertase receptor-destroying enzyme, which may be identical with the that utilized B and D but not P, and that deposited CS on C3b inactivator. particles, probably in the form of C3b (9). Our observations preclude a role of properdin in the initiation of the pathway More thin 20 years ago Pillemer and his associates ap- and lend no support to the concept proposed by Fearon and proached the problem of natural resistance to infections on Austen according to which properdin is required for forma- the molecular level. A novel serum protein, termed proper- tion of the initial CS convertase (12). din, was envisaged to cooperate with hydrazine-sensitive "Factor A" and heat-labile "Factor B" in the activation of Recognition of an initiating factor distinct from complement resulting in natural resistance against certain properdin viruses and bacteria (1, 2). Today we recognize the properdin system or the alterna- Another clue for the existence of a P-independent C3 con- tive pathway of complement activation to consist of five vertase was derived from work on nephritic factor (NF), components: properdin (P) (3), the third component of which is an unusual serum protein occurring in certain ne- complement, C3 (Factor A) (4, 5), proactivator (Factor B) phritides (13). NF associates with B. D, CS, and Mg to form (6), proactivator convertase (Factor D) (5, 7, 8) and the ini- a soluble C3 convertase which is functionally indistinguisha- tiating factor (Factor I or IF) (9), which will be introduced ble from its P-dependent counterpart (14). in this communication as a heretofore unknown component. It was hypothesized that an NF-analogue is present in Four key questions have confronted us during the current normal serum in precursor form and constitutes an essential investigation. First, how is the pathway initiated by such ac- component of the initial CS convertase. An antiserum to NF tivators as bacterial or fungal cell walls? Second, how is pro- was utilized to explore normal serum for the presence of an perdin recruited and what is its function? Third, what is the NF-analogue. Anti-NF-treated serum failed to sustain C3 nature of the enzyme that activates the membrane attack consumption upon prolonged incubation with zymosan. The system of complement? And fourth, what are the regulatory incubated particles, examined by the immunofluorescence principles of the pathway? technique, were devoid of CS and properdin. This totally On the basis of a large body of experimental evidence, negative result was observed in spite of the availability of which will be fully documented elsewhere (9-11), we wish physiological amounts in the serum of P, B, D, CS, and Mg to propose a comprehensive molecular concept of the pro- (Table 1). perdin pathway. In brief, the dynamics of the pathway in- In order to verify that immune absorption had specifically volve assembly of the properdin-receptor-forming enzyme removed an essential component of the properdin system, (PRFE) as a consequence of activation of the initiating fac- the material dissociated from the immune absorbent was tor, assembly of the properdin-activating principle, and for- added back to the absorbed serum. The mixture exhibited zymosan-dependent CS consumption comparable to untreat- ed serum. It was concluded that the factor had been recov- Abbreviations: P, properdin; C, complement, a lower-case letter in- in that it was of restoring the dicates a fragment of a component, an overbar, -, indicates an ered precursor form, capable activated component; IF, initiating factor; PRFE, properdin-recep- impaired serum, and that it therefore must represent an es- tor-forming enzyme; NF, nephritic factor; S, surface site; E, eryth- sential constituent of the properdin system. rocyte; PRDE, properdin-receptor-destroying enzyme Component IF is a pseudoglobulin which behaves as a 612 Downloaded by guest on October 2, 2021 Immunology: Medicus et al. Proc. Nat. Acad. Sci. USA 73 (1976) 613 Table 1. Properdin-independent initiation: Requirements for formation of the properdin-receptor-forming enzyme Deposition on C4-deficient % C3 consumption zymosan* serum Material depleted of added + Zymosan + NaCl C3 P P 22.4 6.9 2+ 0 P, B 2.8 1.8 0 0 P, D 0.6 4.1 0 0 C3 0 0 Me++ (EDTA) 0 0 0 0 IF 1.8 4.5 0 0 IF IF 54.6 7.8 4+ 4+ P, IF 10.1 10.0 0 0 50.0 10.0 4+ 4+ C4 78.6 14.7 4+ 4+ * Twenty microliters of serum, 2 Ml of zymosan (100 Mg), or NaCl and 1 mM Mg+ + were incubated 60 min at 37°. C3 consumption was deter- mined by effective molecule titration, and deposition of C3 and properdin on zymosan was detected with fluorescent antibody. globulin when examined in precursor form by agarose block bound C3b. It is also able to form soluble P-C3 convertase electrophoresis at pH 8.6. It is stable to heating at 560 for 30 together with B, D, CS, and Mg. In serum, P occurs in pre- min and it is distinct from immunoglobulins and properdin cursor form which does not bind directly to C3b and does by immunochemical and physical criteria (9). not form the fluid phase enzyme. Precursor P was obtained The question of the exact role of immunoglobulins in the by a method of purification employing QAE-Sephadex and activation of the pathway is unanswered. Available evidence Sepharose 6B chromatography (11). Using P in radiolabeled indicates that activation by inulin or zymosan may occur in form, it was found that it was bound and activated by the absence of immunoglobulins (9). On the other hand, anti- complex consisting of the properdin receptor and activated body of the IgG class was shown to participate in the initia- Factor B (S-C3b,B, where S denotes a surface site) (10). tion of the pathway by measles-virus-infected cells (15). The reaction proceeds in EDTA and therefore does not re- quire conditions allowing continued formation of S-C3b,B IF-C3 convertase, the properdin-receptor-forming (Table 2). This complex is identical with the previously de- enzyme scribed C3b-dependent C3 convertase which is also known That bound C3b functions as a receptor for properdin has as the feedback enzyme (5, 18). Although the complex has been documented (14, 16). That it is critically involved in an enzymatic function, present evidence suggests that P the activation of properdin will be described below. The en- binding and activation is a non-enzymatic process. For in- zyme responsible for the formation of the receptor, that is, stance, no turnover of P was detected. No activated or irre- for the initial deposition of C3b on activating surfaces, is the versibly inactivated P accumulated in the fluid phase. The IF-C3 convertase (9). The enzyme is generated from activat- loss of precursor from the fluid phase was totally accounted ed IF, B, D, native C3, and Mg. In analogy to the previously for by the amount of specifically bound P. Utilizing differ- described NF-C3 convertase (14), the enzyme may be de- entially radiolabeled B and P and C3b-bearing erythrocytes noted as IF,B,C3; the notation reflects the experimental re- (EC3b), maximally one molecule of P was bound per mole- sult that interactions within the complex occur primarily be- cule of B.
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