Beyond TLR Signaling—The Role of SARM in Antiviral Immune Defense, Apoptosis & Development

Abstract

SARM (Sterile alpha and armadillo motif-containing protein) is the recently identified TIR domain-containing cytosolic protein. Classified as a member of the TLR adaptor family, the multiple locations and functions of SARM (sometimes playing opposing roles), provoke an enigma on its biology. Although originally assumed to be a member of the TLR adaptor family (functioning as a negative regulator of TLR signaling pathway), latest findings indicate that SARM regulates signaling differently from other TLR adaptor proteins. Recent studies have highlighted the significant functional role of SARM in mediating apoptosis and antiviral innate immune response. In this review, we provide an update on the evolutionary conservation, spatial distribution, and regulated expression of SARM to highlight its diverse functional roles. The review will summarize findings on the known interacting partners of SARM and provide analogy on how they add new dimensions to the current understanding on the multifaceted roles of SARM in antiviral activities and apoptotic functions. In addition, we provide a future perspective on the roles of SARM in differentiation and development, with substantial emphasis on the molecular insights to its mechanisms of action.

Emergence of SARM1 as a Potential Therapeutic Target for Wallerian-type Diseases

“…TIR domains are found in other immune cell modulators, including Myeloid Differentiation primary response gene 88 (MyD88), MyD88-adaptor-like protein (Mal), TIR-domain-containing adaptor molecule (TRIF), and TRIF-related adaptor molecule (TRAM) (Figure 2A). In response to various stimuli (e.g., viruses, bacteria, fungi, and protists), Toll-like receptors (TLRs) dimerize and activate intracellular signaling pathways through these TIR-domain-containing adaptor proteins (i.e., MyD88, Mal, TRIF, and TRAM), which ultimately stimulate the transcription and synthesis of proinflammatory cytokines and interferons (Panneerselvam and Ding, 2015).…”

Necroptosis Resumes Apoptosis in Hippocampus but Not in Frontal Cortex

“…This receptor is also a vital sensor for endogenous damage-associated molecular patterns (DAMPs) released from damaged or dying cells. Recent studies show that LPS causes cell death as an agonist for TLR4 and through the amplified TLR4 mRNA level as well [Bi et al, 2014;Festoff, 2014;Panneerselvam and Ding, 2015]. Among programed cell deaths, activated TLR pathway stimulates apoptosis and necroptosis [Gunther et al, 2015].…”

A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity

“…Although axon degeneration-related SARM1 NADase activity has been extensively characterized in neurons (rather than immune cells), it still remains unclear if this enzymatic activity plays a role also in the immune system. However, SARM1 has initially been found to be involved in the innate immunity pathways through the ability of its TIR domain to interact with other proteins, rather than its NADase activity ( O’Neill et al, 2003 ; Panneerselvam and Ding, 2015 ; Carty and Bowie, 2019 ). TIR domains involved in innate immunity pathways form higher-order assemblies and carry out their signaling function through a mechanism termed signaling by co-operative assembly formation (SCAF) ( Nimma et al, 2017 ; Vajjhala et al, 2017 ; Nanson et al, 2019 ).…”