Significance
Upstream cell death stimuli culminate in the activation of an initiator caspase, marking the onset of apoptosis. Activation of the initiator caspase, caspase-9, is mediated by the heptameric Apaf-1 apoptosome. How Apaf-1 apoptosome facilitates the autocatalytic activation of caspase-9 has remained controversial and largely enigmatic. Two contrasting but not mutually exclusive hypotheses, proximity-induced dimerization vs. induced conformation, emphasize different aspects of initiator caspase activation. This study provides compelling evidence to support the induced conformation model for caspase-9 activation. A previously unknown interface between Apaf-1 and caspase-9 was identified to play an essential role in caspase-9 activation, and formation of a multimeric complex between Apaf-1 caspase recruitment domain (CARD) and caspase-9 was shown to be indispensable for caspase-9 activation.
SUMMARY
Proteasome inhibitors have revolutionized outcomes in multiple myeloma, but they are used empirically, and primary and secondary resistance are emerging problems. We have identified TJP1 as a determinant of plasma cell proteasome inhibitor susceptibility. TJP1 suppressed expression of the catalytically active immunoproteasome subunits LMP7 and LMP2, decreased proteasome activity, and enhanced proteasome inhibitor sensitivity in vitro and in vivo. This occurred through TJP1-mediated suppression of EGFR/JAK1/STAT3 signaling, which modulated LMP7 and LMP2 levels. In the clinic, high TJP1 expression in patient myeloma cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration, supporting the use of TJP1 as a biomarker to identify patients most likely to benefit from proteasome inhibitors.
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