They Might Cut It—Lysosomes and Autophagy in Mitotic Progression

Abstract

The division of one cell into two looks so easy, as if it happens without any control at all. Mitosis, the hallmark of mammalian life is, however, tightly regulated from the early onset to the very last phase. Despite the tight control, errors in mitotic division occur frequently and they may result in various chromosomal instabilities and malignancies. The flow of events during mitotic progression where the chromosomes condensate and rearrange with the help of the cytoskeletal network has been described in great detail. Plasma membrane dynamics and endocytic vesicle movement upon deadhesion and reattachment of dividing cells are also demonstrated to be functionally important for the mitotic integrity. Other cytoplasmic organelles, such as autophagosomes and lysosomes, have until recently been considered merely as passive bystanders in this process. Accordingly, at the onset of nuclear envelope breakdown in prometaphase, the number of autophagic structures and lysosomes is reduced and the bulk autophagic machinery is suppressed for the duration of mitosis. This is believed to ensure that the exposed nuclear components are not unintentionally delivered to autophagic degradation. With the evolving technologies that allow the detection of subtle alterations in cytoplasmic organelles, our understanding of the small-scale regulation of intracellular organelles has deepened rapidly and we discuss here recent discoveries revealing unexpected roles for autophagy and lysosomes in the preservation of genomic integrity during mitosis.

Trafficking of Full-Length and N-Terminally Truncated Cathepsin B in Human Colorectal Carcinoma Cells

“…In this context, it is important to note that the anti-cathepsin B signals overlapped with the Draq5™-stained DNA of chromosomes in G2/M phase arrested HCT116 cells (Figure 7E). Thus, this observation is reminiscent of and supportive of the recent elegant work of others, determining an important role for cathepsin B in histone H3 cleavage to enable segregation of chromosomes in late mitotic stages in a pathway that is not connected to pathology, but rather important for regular mitotic cell division [15,48]. Hence, our finding that overexpression of N-terminally truncated cathepsin B, which is sorted into aggresomes, does not interfere with cell cycle progression (Figure 8) not only supports this notion but shows that a better understanding on the spatiotemporal regulation of cathepsin B-mediated proteolysis must be studied in more detail in future by considering physiological and non-physiological conditions alike [12,15,45].…”

“…Cathepsin B belongs to the cysteine peptidases, and is classically regarded as a typical endolysosomal enzyme, although its expression and localization are often altered, particularly in tumor cells. Therefore, it has been linked to tumor cell invasion and metastasis [6][7][8][9][10][11][12][13][14][15][16][17][18]. In normal human cells, cathepsin B mRNA encodes a 47-kDa polypeptide chain which consists of a prepeptide, the signal peptide, a propeptide, and a mature polypeptide chain that can be processed to yield proteolytically active single-and two-chain forms, depending on the removal of an internal propeptide between the light and heavy chains of cathepsin B.…”

Endolysosomal vesicles at the center of B cell activation

“…Interestingly, however, this robust shielding mechanism can be modulated according to altered physiological situations; in mitosis, the architecture changes so that the expression of lysosomal membrane proteins and proteolytic cathepsin enzymes are downregulated, the lysosomal pH increases, and the limiting membranes become more fragile without compromising the cell homeostasis, simultaneously allowing a regulated enzymatic release to the nuclear region via lysosomal membrane permeabilization (Hämälistö et al, 2020;Stahl-Meyer et al, 2022). This suggests that the lysosome regulation can respond to cellintrinsic cues by tuning down protein expression and/or functions, in this case, to shield the exposed genomic content from degradative enzymes (Hämälistö et al, 2021).…”