SARM: From immune regulator to cell executioner.

SARM is the fifth and most conserved member of the Toll/Il-1 Receptor (TIR) adaptor family. However, unlike the other TIR adaptors, MyD88, Mal, TRIF and TRAM, SARM does not participate in transducing signals downstream of TLRs. By contrast SARM inhibits TLR signalling by interacting with the adaptors TRIF and MyD88. In addition, SARM also has positive roles in innate immunity by activating specific transcriptional programs following immune challenge. SARM has a pivotal role in activating different forms of cell death following cellular stress and viral infection. Many of these functions of mammalian SARM are also reflected in SARM orthologues in lower organisms such as C. elegans and Drosophila. SARM expression is particularly enriched in neurons of the CNS and SARM has a critical role in neuronal death and in axon degeneration. Recent fascinating molecular insights have been revealed as to the molecular mechanism of SARM mediated axon degeneration. SARM has been shown to deplete NAD+ by possessing intrinsic NADase activity in the TIR domain of the protein. This activity can be activated experimentally by forced dimerization of the TIR domain. It is thought that this activity of SARM is normally switched off by the axo-protective activities of NMNAT2 which maintain low levels of the NAD+ precursor NMN. Therefore, there is now great excitement in the field of SARM research as targeting this enzymatic activity of SARM may lead to the development of new therapies for neurodegenerative diseases such as multiple sclerosis and motor neuron disease.