Caspase-3 Regulates YAP-Dependent Cell Proliferation and Organ Size

Abstract

Apoptosis culminates in the activation of caspase-3, which plays an important role in implementing the cell death program. Here, we reveal a non-apoptotic role of caspase-3 as a key regulator of cell proliferation and organ size. Caspase-3 is specifically activated in the proliferating cells of the sebaceous gland, but does not instruct cell elimination. Deletion or chemical inhibition of caspase-3 diminishes cell proliferation, decreases cell number and reduces sebaceous gland size in vivo. Exploring the underlying mechanism, we demonstrate that α-catenin is cleaved by caspase-3, thus facilitating the activation and nuclear translocation of yes-associated protein (YAP), a vital regulator of organ size. Accordingly, activation of caspase-3 leads to YAP-dependent organ size augmentation. Finally, we show that X-linked inhibitor of apoptosis protein (XIAP) serves as an endogenous feedback antagonist for the caspase-3/YAP signaling module. Taken together, we report here a molecular mechanism wherein the apoptotic machinery is refocused to regulate cell proliferation and orchestrate organ size.

Homeostasis of the sebaceous gland and mechanisms of acne pathogenesis

“…The outermost part of the SG is comprised of a single‐cell layer, referred to as the peripheral zone, which contains undifferentiated, proliferative presebocytes . The maturation zone consists of several layers of lipid‐droplet‐containing sebocytes.…”

“…The outermost part of the SG is comprised of a single-cell layer, referred to as the peripheral zone, 5 which contains undifferentiated, proliferative presebocytes. 34,35 The maturation zone consists of several layers of lipid-droplet-containing sebocytes. Finally, the 'necrotic' zone contains terminally differentiated sebocytes that undergo nuclear degradation and membrane lysis, resulting in holocrine secretion of lipids ( Fig.…”

Exiting the dark side: A vital role for Caspase-3 in Yap signaling

“…3 Recently, we uncovered an important non-apoptotic function of Caspase-3 in the mouse epidermis. 4 The epidermis is comprised of several compartments: the hair follicle (HF), sweat gland, interfollicular epidermis (IFE) and sebaceous gland (SG). The HF cycles between phases of anagen (growth), catagen (destruction) and telogen (rest), a process fueled by distinct subpopulations of HF stem cells (HFSCs).…”

“…Briefly, proliferating cells situated along the SG proliferative zone (SGPZ) differentiate into lipidfilled sebocytes in the inner SG compartment. 4 As these differentiated sebocytes mature they accumulate lipids, grow in size, erupt and release their sebum. Importantly, while the HF and IFE have been the focus of numerous investigations, extremely little is known regarding homeostasis of the SG and whether it is regulated by apoptotic machinery proteins.…”

“…In fact, the vast majority of these CP3 + SGPZ cells were undergoing proliferation. 4 Since Caspase-3 did not instruct apoptosis in the SG, we utilized Caspase-3 −/mice to examine its function. Caspase-3 −/mice displayed a significant decrease in sebocyte number, as well as a dramatic reduction in SG size.…”