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Lincs Between Inflammasome & Mitochondria

A mitochondrial micropeptide from 1810058I24Rik that is required for NLRP3 activation

by Katherine A. Fitzgerald and colleagues

Original Article

Bhatta, A., Atianand, M., Jiang, Z., Crabtree, J., Blin, J., & Fitzgerald, K. A. (2020). A Mitochondrial Micropeptide Is Required for Activation of the Nlrp3 Inflammasome. The Journal of Immunology, 204(2), 428–437.

(Image excerpted from Bhatta et al. 2020 J Immunol)

The mitochondria has recently been implicated as a site for inflammasome regulation. In case you only have the faintest idea what the inflammasome is, don't fret. From Wikipedia : Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. For further information, please refer to this excellent review by Charles Evavold and Jonathan Kagan. In lay terms, inflammasomes are responsible for helping our immune cells detect danger signs, and activate the appropriate inflammatory pathways to clear the threat. These threats can either originate from microbes, or from molecules that signal tissue damage, stress or cellular imbalance. Here, Bhatta, Fitzgerald and colleagues identify a long non-coding RNA (linc/lnc) that encodes a 47aa peptide Mm47, which when translated, homes to the outer mitochondria membrane and is required for the activation of NLRP3. The mechanism is unclear. The mitochondria is increasingly implicated as the site of inflammasome activation, for instance, via the recruitment of MAVS (Subramanian, N., Natarajan, K., Clatworthy, M. R., Wang, Z., & Germain, R. N. (2013). The Adaptor MAVS Promotes NLRP3 Mitochondrial Localization and Inflammasome Activation. Cell, 153(2), 348–361. Since most mitochondrial peptides function in the context of large complexes (please see work from my lab), the most plausible explanation is that Mm47 is part of the machinery that enables initial oligomerization or cleavage (activation) of NLRP3. Most intriguing and I look forward to the followup! Congrats Katharine and lab!

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