LYZ

LYZ (lysozyme) is classically a secretory antimicrobial muramidase, but the available corpus characterizes additional muramidase-independent activities in cancer and host-pathogen interactions (PMID:37428911, PMID:40253018). In hepatocellular carcinoma, LYZ promotes tumor cell proliferation and migration in both autocrine and paracrine fashion independently of its enzymatic activity, signaling through cell-surface GRP78 (csGRP78) to activate pro-tumoral pathways; its expression in this context is driven by STAT3 activation (PMID:37428911). In the antiviral setting, LYZ acts as a pro-viral host factor: it binds porcine epidemic diarrhea virus NSP8 via its N-terminal domain and downregulates RIG-I transcripts through the m6A reader YTHDF2, thereby blunting IRF3 phosphorylation and nuclear translocation and suppressing IFN-β production (PMID:40253018). Consistent with its classical antibacterial role, host DNA damage responses during typhoid fever trigger LYZ secretion, and secreted LYZ inhibits Salmonella virulence effector secretion and induces bacterial spheroplast formation. Beyond these contexts, no further mechanistic detail has been characterized in the available corpus.

1. 2020 Low

   Linked intestinal LYZ levels to Paneth cell integrity and gut homeostasis, establishing that LYZ expression tracks with Paneth cell populations and influences microbiota and inflammation under estrogen deficiency.

   Evidence Ovariectomy rat osteoporosis model with Paneth cell histology, LYZ quantification, and gut microbiota/cytokine profiling

   PMID:33382620

   Open questions at the time

   • Associative rodent model with no direct reconstitution of LYZ function
   • Does not establish whether LYZ is causal versus a marker of Paneth cell loss
   • No molecular mechanism linking LYZ to microbiota or inflammation
2. 2023 Medium

   Revealed a non-canonical, enzyme-independent pro-tumoral function of LYZ, answering whether lysozyme acts only as a muramidase or also as a signaling ligand in cancer.

   Evidence Knockdown/knockout and overexpression in HCC cells with subcutaneous and orthotopic xenografts in NOD/SCID mice; pathway placement through csGRP78 and STAT3-regulated expression

   PMID:37428911

   Open questions at the time

   • Downstream csGRP78-activated signaling effectors not fully resolved
   • Single lab; muramidase-independence shown but structural basis of csGRP78 binding undefined
   • Generality beyond HCC not established
3. 2025 Medium

   Defined LYZ as a pro-viral host factor that suppresses innate immune signaling, addressing how a viral protein might co-opt LYZ to evade interferon responses.

   Evidence IP-MS and reciprocal co-IP with PEDV NSP8, confocal colocalization, domain-deletion mapping, and viral replication/IRF3 phosphorylation/IFN-β readouts

   PMID:40253018

   Open questions at the time

   • Mechanism by which LYZ-NSP8 interaction triggers YTHDF2-mediated RIG-I transcript degradation not resolved
   • Single lab; whether endogenous LYZ recapitulates the effect in vivo unclear
   • Relevance to human viral infections not tested
4. 2024 Medium

   Connected host DNA damage signaling to LYZ secretion and demonstrated a direct antibacterial action against Salmonella, clarifying how the classical antimicrobial role is regulated during systemic infection.

   Evidence Plasma proteomics from bacteraemic participants, recombinant typhoid toxin treatment, and recombinant LYZ bacterial morphology and effector-secretion assays (preprint)

   Open questions at the time

   • Preprint; not yet peer-reviewed
   • ATM/ATR-to-secretion signaling steps not mechanistically dissected
   • Whether spheroplast formation reflects muramidase activity or another mechanism not resolved

• How LYZ's muramidase-independent signaling functions mechanistically integrate with its classical enzymatic antimicrobial role across tissues remains unresolved.
• No unifying model linking enzymatic and non-enzymatic activities
• Structural basis of csGRP78 and NSP8 binding undefined
• Tissue- and context-specific regulation of LYZ secretion not characterized