The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis

Abstract

Diabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.

Apoptosis in Type 2 Diabetes: Can It Be Prevented? Hippo Pathway Prospects

“…Many studies emphasize that pancreatic β cells are extremely sensitive to oxidative stress due to the low level of antioxidant enzymes (catalase, glutathione peroxidase and superoxide dismutase) [ 23 ]. The involvement of the Hippo pathway in the regulation of the apoptotic process resulting from the metabolic changes associated with type 2 diabetes has been documented on the basis of the contribution of its individual elements, including MST1 [ 64 ], Merlin (Nf2) [ 65 ], LATS2 [ 46 , 66 ], and YAP [ 65 , 67 ].…”

“…LATS-regulated cell apoptosis also affects downstream targets, the most common of which are P53, FOXO1, abelson tyrosine kinase c-Abl (c-Abl), and YAP [ 135 , 136 , 137 ]. LATS is a critical component of the Hippo pathway for the induction of apoptosis in β cells [ 46 ]. Its mechanism of action is based on the mechanistic target of rapamycin 1 (mTORC1).…”

“…It is thought to mediate β cell growth and expansion [ 138 ]. However, its excessive activation and negative effects related to the loss of β cells were revealed in animal models showing the presence of type 2 diabetes [ 46 ], clearly pointing to an ongoing apoptosis scenario, in which the presence of conditions leading to diabetes activates the sequelae cascade, i.e., diabetic conditions activate the LATS and thereby activate mTORC1 by suppressing AMP-activated protein kinase (AMPK) signaling. Moreover, growing evidence suggests that AMP-activated protein kinase (AMPK) and mTOR play a pivotal role in autophagy and apoptosis [ 140 ].…”

“…Research focused on the role of LATS1/2 in the process of the apotosis of pancreatic β cells is still carried using a conventional understanding of the mechanism of regulation of this kinase in this process. Yuan et al [ 46 ] showed that large tumor suppressor 2 (LATS2) induces apoptosis, but also affects pancreatic β cells by participating in the development of apoptosis. The action of this isoform is revealed in diabetic states.…”

“…Although the mechanism of apoptosis has been identified at many levels (expression of apoptosis genes, triggering, initiation of signaling cascades) [ 43 ], in the treatment of type 2 diabetes, targeted action on its arrest has not been introduced. Intensive research in recent years shows a promising prognosis and probably the therapeutic basis for the use of the Hippo pathway [ 44 , 45 , 46 ]. It was proven that the general components and functions identified in the Hippo pathway are involved in regulating organ size by maintaining a balance between apoptosis, proliferation, and cell/tissue regeneration [ 47 , 48 ].…”