TSPAN33

TSPAN33 (Penumbra) is a cell-surface tetraspanin that links membrane proteolysis to hematopoietic and inflammatory programs (PMID:17158226, PMID:27574297). It is synthesized as a 283-residue protein that traffics to the cell surface and assembles into disulfide-bonded homodimers, and is required for normal erythropoiesis: loss in mice produces splenomegaly, macrocytic anemia, and ineffective erythropoiesis, while re-expression restores erythropoietin-driven erythroid differentiation in knockout cells (PMID:17158226). As a TspanC8 tetraspanin, TSPAN33 promotes maturation of the metalloprotease ADAM10 (but not ADAM17), thereby enhancing NOTCH processing at the membrane (PMID:27574297). In macrophages its own expression is induced by TLR (TLR2/3/4) and IFN-γ signaling in a NOTCH-dependent manner, and it amplifies NF-κB-dependent proinflammatory transcription, positioning it as a positive feedback regulator of the NOTCH/ADAM10 axis during inflammatory activation (PMID:27574297). It is absent from resting B cells but strongly induced upon B cell activation and is expressed in several lymphomas and in B cells of autoimmune patients, marking activated and malignant B cells (PMID:24211713).

1. 2006 High

   Established TSPAN33 as a bona fide cell-surface tetraspanin with a non-redundant, positive role in erythroid differentiation, answering whether this novel gene had a defined physiological function.

   Evidence Knockout mouse with anemia/ineffective erythropoiesis phenotype, cell-surface targeting and disulfide-bond assays, and re-expression rescue of EPO-driven erythroid differentiation in a Penumbra-/- cell line

   PMID:17158226

   Open questions at the time

   • Molecular partners mediating the erythropoietic effect not identified
   • No link to ADAM10/NOTCH established in this context
2. 2013 Medium

   Extended TSPAN33 beyond erythropoiesis by showing it is an activation-induced marker of B cells and is expressed in lymphomas and autoimmune B cells, raising the question of its role in adaptive immunity.

   Evidence Expression profiling of resting vs. activated primary human B cells, flow cytometry/immunostaining of B cell lines, lymphoma samples, and MRL/Fas(lpr/lpr) mouse B cells

   PMID:24211713

   Open questions at the time

   • Mechanistic role in B cell activation or transformation not defined
   • Correlative expression only; no functional perturbation
3. 2016 High

   Defined the molecular mechanism by which TSPAN33 acts in macrophages, placing it in a TLR/NOTCH-induced feedback loop that promotes ADAM10 maturation and amplifies NOTCH and NF-κB signaling.

   Evidence Reciprocal overexpression/knockdown in macrophages, Notch1/Notch2-deficient macrophages, constitutively active NOTCH1, ADAM10/ADAM17 maturation westerns, NF-κB reporter and TLR ligand stimulation assays

   PMID:27574297

   Open questions at the time

   • Whether the same ADAM10/NOTCH mechanism underlies the erythroid and B cell phenotypes is untested
   • Direct physical interaction between TSPAN33 and ADAM10 not biochemically resolved here
   • No structural basis for ADAM10 selectivity over ADAM17

• Whether the ADAM10/NOTCH-promoting activity defined in macrophages mechanistically explains TSPAN33's roles in erythropoiesis and in B cell activation/malignancy remains unresolved.
• No unifying mechanism connecting erythroid, B cell, and macrophage functions
• Erythropoiesis-relevant substrates or partners unknown