Lethal factor (LF), which constitutes one of the three proteins composing the anthrax toxin, is able to trigger rapid cell death in macrophages (PubMed:3711080, PubMed:8380282, PubMed:9563949, PubMed:10475971, PubMed:11104681, PubMed:9703991). Acts as a protease that cleaves the N-terminal of most dual specificity mitogen-activated protein kinase kinases (MAPKKs or MAP2Ks) (except for MAP2K5): cleavage invariably occurs within the N-terminal proline-rich region preceding the kinase domain, thus disrupting a sequence involved in directing specific protein-protein interactions necessary for the assembly of signaling complexes (PubMed:9563949, PubMed:10475971, PubMed:11104681, PubMed:9703991, PubMed:14718925). Also cleaves mouse Nlrp1b: host Nlrp1b cleavage promotes ubiquitination and degradation of the N-terminal part of Nlrp1b by the proteasome, thereby releasing the cleaved C-terminal part of Nlrp1b, which polymerizes and forms the Nlrp1b inflammasome followed by host cell pyroptosis (PubMed:10338520, PubMed:19651869, PubMed:31268597, PubMed:30872531). Able to cleave mouse Nlrp1b alleles 1 and 5, while it is not able to cleave Nlrp1b alleles 2, 3 and 4 (PubMed:16429160, PubMed:19651869). In contrast, does not cleave NLRP1 human ortholog (PubMed:19651869). LF is not toxic by itself and only acts as a lethal factor when associated with protective antigen (PA) to form the lethal toxin (LeTx): PA is required for LF translocation into the host cytosol (PubMed:9563949, PubMed:10475971, PubMed:11104681, PubMed:9703991). Preferred amino acids around the cleavage site can be denoted BBBBxHx-|-H, in which B denotes Arg or Lys, H denotes a hydrophobic amino acid, and x is any amino acid. The only known protein substrates are mitogen-activated protein (MAP) kinase kinases. Binds 1 zinc ion per subunit. Inhibited by NSC-12155 (1,3-Bis(2-methyl-4-aminoquinoline-6-yl)ure) (PubMed:14718925). Inhibited by phenoxyacetic acid bearing alpha-benzyl substituents on the C2-side chain (PubMed:22342144). Inhibited by sulfonamide hydroxamate with benzylic additions at the sulfonamide nitrogen (PubMed:25372673). Also inhibited by sulfonamide hydroxamates with alkylation at the sulfonamide nitrogen (PubMed:26492514). Inhibited by hydroxamic acid inhibitors (PubMed:26578066). Interacts (via ATLF domain 1) with the cleaved form of protective antigen (PA-63) anthrax toxin; interaction is required for LF translocation into the host cytoplasm (PubMed:10085027, PubMed:8942659, PubMed:15313199, PubMed:21037566, PubMed:32047164, PubMed:32810181, PubMed:32521227). Interacts with PA-63 homooligomers (either homoheptamers or homooctamers): three molecules of LF bind the PA-63 homoheptamer to form the PA(7)LF(3) complex, in which the relative position of the N-terminal alpha-helices in the three LFs determines which factor is translocated first (PubMed:32810181). Translocation into host cytosol is mediated via interaction with the cleaved form of protective antigen (PA-63): following secretion, LF binds via its N-terminal region to the upper rim of the ring-shaped homooligomer formed by PA-63 on the host cell membrane (PubMed:21037566, PubMed:32810181). In this PA-63 pre-pore state, the N-terminal segment of LF refolds into an alpha helix engaged in the alpha-clamp of the PA-63 pre-pore (PubMed:32047164, PubMed:32521227). Loaded complexes are then endocytosed, followed by a conformational change of oligomerized PA-63 from the pre-pore to pore state, which is triggered by the low pH in the endosome (PubMed:3711080, PubMed:8380282, PubMed:10085027, PubMed:12551953). LF is then unfolded to pass through the PA-63 pore and translocate into the host cytosol (PubMed:21037566, PubMed:32047164, PubMed:32521227). Positively transcriptionally regulated by AtxA, which, in turn, is induced by bicarbonate and high temperatures (37 degrees Celsius). Lethal factor (LF) is composed of four domains: domain I contains the first ATLF domain that binds the membrane-translocating component protective antigen (PA); domains II, III and IV together create a long deep groove that holds the 16-residue N-terminal tail of MAPKK before cleavage (PubMed:11700563). Domain IV contains the catalytic center (PubMed:11700563). Belongs to the peptidase M34 family.