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Alex Gitlin

@gitlinlabmsk.bsky.social

602 followers 229 following 17 posts

Assistant Member/Professor, Lab Head @MSKCancerCenter. #PhysicianScientist #Immunologist. Views my own.

Alex Gitlin @gitlinlabmsk.bsky.social · 04/11/2025

And finally, molecularly, this cell death phenotype correlated with a marked kinetic defect in the Lys63/Linear polyubiquitylation of inflammatory signaling complexes, linking VEXAS with other rarer germline disorders affecting LUBAC, OTULIN, etc 11/

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Alex Gitlin @gitlinlabmsk.bsky.social · 04/11/2025

Secondly, Uba1 M41T mutation either in mouse or human HSPCs triggered a pronounced myeloid bias and an unfolded protein response, as described in the initial NEJM report - notably, this was independent of cell death as it still occurred in RIPK3-Casp8 deficient mutant cells 10/

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Alex Gitlin @gitlinlabmsk.bsky.social · 04/11/2025

First, we found that across all mutation types tested (M41T, M41V, splice site mutants), Uba1 mutant macrophages showed aberrant apoptotic and necroptotic responses to stimulation with inflammatory triggers like TNF and LPS - through the RIPK3-MLKL-Casp8 axis. 9/

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Alex Gitlin @gitlinlabmsk.bsky.social · 04/11/2025

This worked surprisingly well in pools of primary macrophages and we even saw the VEXAS-like diminution of UBA1b and expression of UBA1c, so we were off to the races to try to figure out what was happening molecularly/cellularly. 8/

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Alex Gitlin @gitlinlabmsk.bsky.social · 04/11/2025

Strikingly, Beck et al found that these somatic mutations occurred in hematopoietic stem/progenitor cells (HSPCs) and their myeloid, but not lymphoid, progeny - leading to progressive bone marrow failure and severe multiorgan autoinflammation. 5/

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Alex Gitlin @gitlinlabmsk.bsky.social · 04/11/2025

So what are these mutations? Beautiful work from Beck et al in the NEJM paper showed Met41 mutations selectively impair translation initiation that normally generates the UBA1b isoform, leading to aberrant initiation at Met67 instead - generating an impaired isoform, UBA1c. 4/

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