Death domain fold proteins in immune signaling and transcriptional regulation

Abstract

Death Domain Fold (DDF) superfamily comprises of the death domain (DD), death effector domain (DED), caspase activation recruitment domain (CARD) and pyrin domain (PYD). By utilizing a conserved mode of interaction involving six distinct surfaces, a DDF serves as a building block that can densely pack into homo-multimers or filaments. Studies of immune signaling components have revealed that DDF-mediated filament formation plays a central role in mediating signal transduction and amplification. The unique ability of DDFs to self-oligomerize upon external Accepted ArticleThis article is protected by copyright. All rights reserved signals and induce oligomerization of partner molecules underlies key processes in many innate immune signaling pathways, as exemplified by RIG-I-like receptor signalosome and inflammasome assembly. Recent studies showed that DDFs are not limited to immune signaling pathways, but also are involved with transcriptional regulation and other biological processes. Considering that DDF annotation still remains a challenge, the current list of DDFs and their functions may represent just the tip of the iceberg within the full spectrum of DDF biology. In this review, we discuss recent advances in our understanding of DDF functions, structures and assembly architectures with a focus on CARDand PYD-containing proteins. We also discuss areas of future research and the potential relationship of DDFs with biomolecular condensates formed by liquid-liquid phase separation (LLPS).

An integrative multi-omics analysis based on liquid–liquid phase separation delineates distinct subtypes of lower-grade glioma and identifies a prognostic signature

“…Evidence is now mounting that LLPS process plays an integral role in the tumorigenesis and progression [ 17 ]. Moreover, the formation of different TIME patterns has also been shown to be correlated with LLPS due to its involvement in the regulation of immune signaling [ 34 , 35 ]. Therefore, we supposed that a comprehensive exploration of LLPS-related biomarkers held great promise for the identification of novel subtypes of tumors, and the prediction of prognosis and immunotherapeutic response.…”

Identification of molecular subtypes based on liquid–liquid phase separation and cross-talk with immunological phenotype in bladder cancer

“…However, the different functions of LLPS in cancer are still unclear. Studies have shown that LLPS could aid in deciphering the heterogeneity of TME ( 34 ), exploring genomic alterations and transcriptional aberrations ( 35 ), and the impact of drug distribution into condensate ( 36 ). LLPS plays multiple roles in carcinogenesis; therefore, identifying LLPS-related biomarkers could offer important insights into defining tumor subtypes and evaluating the prognoses of patients.…”

Infection and immunity: ‘There Are Things Out There You (Don't) Need To Know About’

“…Mia and Singh [12] discuss how an evolutionary conserved Hippo pathway regulates the proliferation and differentiation of macrophages and epithelial cells in the diverse settings of cardiovascular, pulmonary, liver and gut inflammation, and neuroinflammation. One of the key events in numerous intracellular signalling pathways is the formation of the aggregate‐like macromolecular signalling hub often nucleated by the members of the death domain fold (DDF) superfamily of proteins, extensively reviewed by Huoh and Hur [13]. While for a long time viewed as an inactive misfolded protein depot, it is now clear that the formation of these filamentous macromolecular complexes is essential for the correct concentration and sequestration of effector molecules enabling signal transduction.…”