Role of ADAM10 and ADAM17 in Regulating CD137 Function

Abstract

Human CD137 (4-1BB), a member of the TNF receptor family, and its ligand CD137L (4-1BBL), are expressed on immune cells and tumor cells. CD137/CD137L interaction mediates bidirectional cellular responses of potential relevance in inflammatory diseases, autoimmunity and oncology. A soluble form of CD137 exists, elevated levels of which have been reported in patients with rheumatoid arthritis and various malignancies. Soluble CD137 (sCD137) is considered to represent a splice variant of CD137. In this report, however, evidence is presented that A Disintegrin and Metalloproteinase (ADAM)10 and potentially also ADAM17 are centrally involved in its generation. Release of sCD137 by transfected cell lines and primary T cells was uniformly inhibitable by ADAM10 inhibition. The shedding function of ADAM10 can be blocked through inhibition of its interaction with surface exposed phosphatidylserine (PS), and this effectively inhibited sCD137 generation. The phospholipid scramblase Anoctamin-6 (ANO6) traffics PS to the outer membrane and thus modifies ADAM10 function. Overexpression of ANO6 increased stimulated shedding, and hyperactive ANO6 led to maximal constitutive shedding of CD137. sCD137 was functionally active and augmented T cell proliferation. Our findings shed new light on the regulation of CD137/CD137L immune responses with potential impact on immunotherapeutic approaches targeting CD137.

Construction and Validation of a Novel Pyroptosis-Related Gene Signature to Predict the Prognosis of Uveal Melanoma

“…Their study demonstrated the role of ANO6 in macrophage-associated immune defense. Seidel et al found that ANO6 may be involved in the regulation of CD137/CD137L immune response and may have an impact on immunotherapy approaches targeting CD137 (Seidel et al, 2021). Therefore, ANO6 has potential significance in tumor immunity.…”

Scramblases as Regulators of Proteolytic ADAM Function

“…A soluble form of CD137 (sCD137), hitherto considered to represent a splice variant of the membrane-anchored molecule, circulates and is elevated in plasma of patients with rheumatoid arthritis and diverse malignancies [78][79][80]. A directed search led to the finding that ADAM10 is centrally involved in the generation of sCD137 [33]. Release of sCD137 was markedly suppressed when ADAM10 sheddase function was inhibited by either conventional inhibitors or through the presence of soluble phosphorylserine.…”

“…We summarize current knowledge regarding the significance of PS externalization on proteolytic activity of ADAM10 and ADAM17. Arguments are presented to support the concept that scramblase-mediated shuffling of phospholipids is a key step leading to ADAM10 and ADAM17 activation [30][31][32][33][34][35]. The potential functional consequences of these interactions are discussed and future challenges to be met in field are outlined.…”

N-Glycosylation Facilitates 4-1BB Membrane Localization by Avoiding Its Multimerization

“…The clinical development of two 4-1BB agonistic antibodies, namely urelumab and utomilumab, is ongoing for anti-tumor purposes [ 17 ]. It has also been reported that the secreted form of 4-1BB, which is generated through either alternative mRNA splicing or cleavage by membrane-bound metalloproteases [ 18 , 19 ], diminishes the 4-1BB/4-1BBL axis by competing against the T cell functional surface 4-1BB.…”