Mst1 knockout enhances cardiomyocyte autophagic flux to alleviate angiotensin II-induced cardiac injury independent of angiotensin II receptors
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Authors: Cheng, Zheng; Zhang, Mingming; Hu, Jianqiang; Lin, Jie; Feng, Xinyu; Wang, Shanjie; Wang, Tingting; Gao, Erhe; Wang, Haichang; Sun, Dongdong
Abstract
Aims: Angiotension II (Ang II) plays a central role in the pathogenesis of renin-angiotensin-aldosterone system (RAAS)-induced heart failure. Mst1 exerts its function in cardiomyocytes subjected to pathological stimuli via inhibiting autophagy and aggravating apoptosis, but its role in RAAS-mediated cardiac injury is still unknown. Here, we aimed to determine whether cardiomyocyte-specific Mst1 knockout can alleviate Ang II-induced cardiac injury by improving cardiomyocyte autophagy and whether these functions depend on Ang II receptors. Results: Mst1 knockout alleviated Ang II-induced heart failure, without affecting blood pressure and compensatory concentric hypertrophy. Mst1 specific knockout improved the effects of Ang II on cardiomyocyte autophagy, as evidenced by further increased LC3-II expression and decreased P62 expression. More typical autophagosomes accompanied by less damaged mitochondria were also observed by electron microscopy in Ang II-treated Mst1(Delta/Delta) mice. In vitro, Mst1 knockdown promoted cardiomyocyte autophagic flux, as demonstrated by more GFP-mRFP-LC3 puncta per cell. Increased LC3-II and decreased P62 expression both in the presence and absence of chloroquine were observed in Mst1 knockdown cardiomyocytes administered with Ang II. Treatment with 3-MA, an inhibitor of autophagy, abolished the beneficial effects of Mst1 knockout against Ang II-induced cardiac dysfunction. The compensatory effects of Ang II on upregulated autophagy were associated with Mst1 inhibition. Interestingly, the knockdown or antagonization of AT(1)R inhibited cardiomyocyte autophagy, which may represent a threat to cardiac function. Importantly, Mst1 knockout consistently enhanced cardiomyocyte autophagy following the knockdown or blocking of AT(1)R and AT(2)R. Conclusion: Cardiomyocyte-specific Mst1 knockout alleviates Ang II-induced cardiac injury by enhancing cardiomyocyte autophagy. Mst1 inhibition may counteract the undesirable effects of Ang II receptors blockage on cardiomyocyte autophagy and represent a promising complementary treatment strategy against Ang II-induced cardiac injury.
The Legionella Effector Kinase LegK7 Hijacks the Host Hippo Pathway to Promote Infection
CELL HOST & MICROBE
Authors: Lee, Pei-Chung; Machner, Matthias P.
Abstract
The intracellular pathogen Legionella pneumophila encodes translocated effector proteins that modify host cell processes to support bacterial survival and growth. Here, we show that the L. pneumophila effector protein LegK7 hijacks the conserved Hippo signaling pathway by molecularly mimicking host Hippo kinase (MST1 in mammals), which is the key regulator of pathway activation. LegK7, like Hippo/MST1, phosphorylates the scaffolding protein MOB1, which triggers a signaling cascade resulting in the degradation of the transcriptional regulators TAZ and YAP1. Transcriptome analysis revealed that LegK7-mediated targeting of TAZ and YAP1 alters the transcriptional profile of mammalian macrophages, a key cellular target of L. pneumophila infection. Specifically, genes targeted by the transcription factor PPAR gamma, which is regulated by TAZ, displayed altered expression, and continuous interference with PPAR gamma activity rendered macrophages less permissive to L. pneumophila intracellular growth. Thus, a conserved L. pneumophila effector kinase exploits the Hippo pathway to promote bacterial growth and infection.
COA
Publication 
Loading ......
