Altered endocytosis in cellular senescence

Abstract

Cellular senescence occurs in response to diverse stresses (e.g., telomere shortening, DNA damage, oxidative stress, oncogene activation). A growing body of evidence indicates that alterations in multiple components of endocytic pathways contribute to cellular senescence. Clathrin-mediated endocytosis (CME) and caveolae-mediated endocytosis (CavME) represent major types of endocytosis that are implicated in senescence. More recent research has also identified a chromatin modifier and tumor suppressor that contributes to the induction of senescence via altered endocytosis. Here, molecular regulators of aberrant endocytosis-induced senescence are reviewed and discussed in the context of their capacity to serve as senescence-inducing stressors or modifiers.

Keywords: Amphiphysin; Caveolin-1; Endocytosis; ING1; Senescence; βPAK-interacting nucleotide exchange factor (βPIX).

Fig. 1.

A model for the role of βPIX/GIT complex and CME in senescence. βPIX/GIT complex and calpain 2 localize to focal adhesions by binding to paxillin, which inhibits calpain 2 binding to paxillin, thus preventing calpain 2-mediated cleavage of amphiphysin 1 (left panel). Internalization of β1 integrin via CME maintains normal integrin signaling (left panel). Reduced levels of the βPIX/GIT complex in senescent cells allow calpain 2 binding to paxillin, resulting in cleavage of amphiphysin 1 (right panel, ①②). Excessive accumulation of cell surface active β1 integrin results in persistent and abnormal signaling, including excessive ROS, which accelerates senescence (right panel,③④).

Fig. 2.

A model for ING1-induced senescence. ING1b regulates p53 function and epigenetic control by modulating chromatin structure (①②). ING1a upregulates ITSN2 through epigenetic control (②), which in turn inhibits CME (③). This may result in activation of integrin signaling, while inhibiting EGFR signaling. Downstream of these signaling events, the p16/Rb pathway induces cell cycle arrest and senescence (③④). It is yet unclear whether ING1b also blocks CME via ITSN2.

Fig. 3.

A model for Cav1-induced senescence. In general, caveolar Cav1 recruits signaling molecules mediated by interactions with its scaffolding domain and sequesters them into an inactive state. Non-caveolar Cav1 can be produced by dissociation of caveolae in response to mechanical stress (Sinha et al., 2011) (①), or when caveolins are overexpressed (Hayer et al., 2010; Parton and Howes, 2010) (②). This pool can translocate to focal adhesions where it can form oligomers with β1 integrin, which results in integrin activation (Kawabe et al., 2004). Non-caveolar Cav1 is also present in diverse cellular compartments where it regulates distinct pathways including integrin activation and function (Head and Insel, 2007; Pol et al., 2020).

Fig. 4.

A model for the central role of integrin activation in aberrant endocytosis-induced senescence. Reduced βPIX/GIT complex and upregulated ING1a inhibit CME, which results in activation of integrin signaling (①②). Caveolar and non-caveolar Cav1 contribute to integrin activation, though it is unclear to what extent they do (③④). This model highlights the complex interplay between key endocytic proteins and senescence regulators. Overall, reduced endocytosis that deregulates signaling of membrane receptors may be a common mediator for multiple senescence pathways.