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The thyroid gland is both a thyroid hormone (TH) generating as well as a TH responsive
organ. It is hence crucial that cathepsin-mediated proteolytic cleavage of the precursor thyroglobulin
is regulated and integrated with the subsequent export of TH into the blood circulation, which is
enabled by TH transporters such as monocarboxylate transporters Mct8 and Mct10. Previously, we
showed that cathepsin K-deficient mice exhibit the phenomenon of functional compensation through
cathepsin L upregulation, which is independent of the canonical hypothalamus-pituitary-thyroid axis,
thus, due to auto-regulation. Since these animals also feature enhanced Mct8 expression, we aimed
to understand if TH transporters are part of the thyroid auto-regulatory mechanisms. Therefore,
we analyzed phenotypic differences in thyroid function arising from combined cathepsin K and
TH transporter deficiencies, i.e., in Ctsk-/-/Mct10-/-
, Ctsk-/-/Mct8-/y, and Ctsk-/-/Mct8-/y/Mct10-/-
.
Despite the impaired TH export, thyroglobulin degradation was enhanced in the mice lacking Mct8,
particularly in the triple-deficient genotype, due to increased cathepsin amounts and enhanced cysteine peptidase activities, leading to ongoing thyroglobulin proteolysis for TH liberation, eventually
causing self-thyrotoxic thyroid states. The increased cathepsin amounts were a consequence of
autophagy-mediated lysosomal biogenesis that is possibly triggered due to the stress accompanying
intrathyroidal TH accumulation, in particular in the Ctsk-/-/Mct8-/y/Mct10-/- animals. Collectively,
our data points to the notion that the absence of cathepsin K and Mct8 leads to excessive thyroglobulin
degradation and TH liberation in a non-classical pathway of thyroid auto-regulation.
Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant, which may contribute to human ACTN2-associated cardiomyopathies.
Over the past 10 years, the crisis of sepsis has remained a great challenge. According to data from 2016, the sepsis-related mortality rate remains high. In addition, sepsis consumes extensive medical resources in intensive care units, and anti-inflammatory agents fail to improve sepsis-associated hyperinflammation and symptoms of immunosuppression. The specific immune mechanism of sepsis remains to be elucidated. Reactive oxygen species (ROS) are triggered by energy metabolism and respiratory dysfunction in sepsis, which not only cause oxidative damage to tissues and organelles, but also directly and indirectly promote NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. NLRP3 inflammasomes enlarge the inflammatory response and trigger apoptosis of immune cells to exacerbate sepsis progression. Inhibiting the negative effects of ROS and NLRP3 inflammasomes therefore provides the possibility of reversing the excessive inflammation during sepsis. In this review, we describe the interaction of ROS and NLRP3 inflammasomes during sepsis, provide prevention strategies, and identify fields that need further study.