Thread by @connor_rosen

Extremely exciting findings from @russellevance and @DBachovchin labs on NLRP1 activation following cleavage and degradation of N-terminal fragment now on biorxiv - biorxiv.org/content/early/… and biorxiv.org/content/early/… (1/9)

Destabilization of NLRP1b (e.g. cleavage by bacterial protease or degradation by bacterial ubiquitin ligase) releases non-covalently linked C-terminal fragment that can activate inflammasomes - caspase-1, pyroptosis, IL-1b, the works. (2/9)

Awesome mechanism for maintaining auto inhibition with associated fragments after auto-catalytic cleavage, and exploiting processive nature of the proteasome - using Nlrp1b as a “decoy sensor” sensing its own stability, a molecular "booby trap". (3/9)

Also raises something I’ve found very interesting for a long time - is there a general role of the N-end rule pathway in sensing and responding to pathogens? (4/9)

N-end rule responds (mainly) to cleaved or N-terminally exposed proteins - allowing it to act as a sensor of unusual proteolytic activity and aberrant cytosolic localization of extracellular proteins. (5/9)

Could the N-end rule sensation of “foreign” proteolytic activity be a broad mechanism for initiation of immunity in a cell-intrinsic manner? Is it acting as a coordinator of protease sensing? (6/9)

The N-end rule is evolutionary ancient - well characterized from bacteria to plants to mammals. And threat of foreign protease activity / protein injection is also universal - from toxins / T6SS effectors in bacteria through to LT and IpaH7.8 here. (7/9)

N-end rule could be acting in many ways - cleavage of proteins secreted into a cell by recognizing post-signal-peptide N-terminii - or, as these preprints demonstrate spectacularly, by controlling stability of a sensor of foreign proteolytic activity. (8/9)

Congrats to everyone involved in both groups, love the stories and thanks for sharing #ASAPBio! #Inflammasomes #InnateImmunity #HostPathogen (9/9)