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)
Here’s a thread on anti-interferon autoantibodies, viral infections, and human immunology. This is less a covid thread, and more an anti-covid thread, if anything…
Summary: anti-IFN auto-Abs may be reflective of chronic inflammation, and may pre-exist in vulnerable groups at high levels. Presence in severe covid cases may therefore reflect basal immune variation which impacts covid, rather than a special covid-specific phenomenon.
This is prompted based on the new Science paper on autoantibodies against Type I IFNs in severe covid patients (science.sciencemag.org/content/early/…). Basically, ~10% of severe covid patients had high titer anti-IFNa antibodies that were functionally neutralizing.
I'm grateful that others have put together resources like bit.ly/ANTIRACISMRESO…, which has helped me learn to be better. So You Want To Talk About Race by @IjeomaOluo and How To Be An Antiracist by @DrIbram have been amazing, and I'm looking forward to reading deeper.
I haven't seen a similar central resource for donations, but various recommendations led me to eji.org (Equal Justice initiative, focused on criminal justice reform and education), voterparticipation.org (get people registered to vote)...
The original paper, which was mainly based on the temperature-dependent fluorescence of a mitochondria-targeting probe, was accompanied by a “Primer” (journals.plos.org/plosbiology/ar…) highlighting potential flaws and implications, a special sort-of-peer-review step by PLOS Biology.
This new awesome resource @naturemethods - nature.com/articles/s4159… - offers some intriguing orthogonal validation. This is a proteome-wide study of protein thermal stability across 13 organisms, conducted using a mass-spec-based approach.
Super neat story on how cellular quality control impacts the mutational landscape of proteins - beneficial mutations in DHFR during deep mutational scanning are totally altered dependent on cellular QC #Biophysics#Evolutionbiorxiv.org/content/10.110… Way to go! @KortemmeLab
In an initial DMS experiment on DHFR, there were a large number (25% of all sequences!) of advantageous mutations spread across the whole protein. Reintroduction of QC protein Lon reduced the number of advantageous mutants and lowered average benefit of those mutations
Changes in selection coefficient (the “advantageous-ness”) were most striking at hydrophobic/aromatic residues and buried residues - and these correlate with Tm changes of variants. So Lon seems to be imposing higher standards on DHFR, particularly for destabilizing core mutants
A couple interesting bits of preliminary data on Langerhans cells and the huLangerin mouse used to study them. Effects of developmental absence of LCs on keratinocytes and T cells, and huLangerin-YFP labels some neurons (check your Cre mice!) #Genetics#Immunology
First - effect of loss of LCs in the huLangerin-DTA mice - biorxiv.org/content/10.110…. Bulk RNA-seq showed changes in keratinocytes and dendritic epidermal T cells, including cell-type specific changes (e.g. loss of IL17 pathway in DETCs).
Unfortunately, underlying data (either gene expression tables or raw RNA-seq data) don’t currently seem available, but hopefully the authors get that up shortly. Will be interesting to look at and prompt some hypotheses about how LCs control homeostasis and development.
CYTOF analysis of human neutrophils - 7 populations with differing phagocytosis, ROS, and FACS-compatible surface marker phenotypes. Changes in distribution between healthy + melanoma patients. #Immunology#Cancer#Neutrophilsbiorxiv.org/content/10.110…
Circulating neutrophil precursors, aged neutrophils, and a few populations of mature and immature neutrophils. Melanoma stage correlates with loss of dominant N2 (mature, ROS++, lowly phagocytic), and increase of N5 (immature, non-proliferative, ROS+, lowly phagocytic).
Interesting to note the phagocytosis-SSC staining in Fig4A - big changes in SSC for some populations with zymosan, others not so much - degranulation, different phagosomes…? Similarly, bimodal peaks for ROS production in same populations…