How does a cell remodel its proteome with cell size?

Motivation

Cells grow to change their protein composition — but how? Does it matter?

One of the most fundamental assumptions in cell biology is that as cells grow larger, the concentrations of proteins and RNAs remain constant. The thought is that a large cell is just a bigger version of its smaller self. This assumption underlies most models of cell-cycle control and homeostasis.

We recently found that this assumption is not true. Cells remodel their proteome as they get larger, such that individual proteins scale differently with size. Bigger cells were also found to be less proliferative and more prone to DNA damage.¹

How does the cell coordinate this differential scaling of individual proteins? Are there other physiological consequences for the cell in becoming larger?

Why it matters

Cell size itself may be a driver of senescence, not just a bystander

Senescent cells — cells that have permanently exited the cell cycle — are characteristically large. The conventional interpretation is that this is a passive consequence: cells that stop dividing continue to grow, accumulating mass without distributing it.

Previous findings in our lab challenge this view.^1,2,3 Concentration changes across the proteome resemble those of senescent cells even in a near twofold size range. This raises the possibility that large size is not merely a result of senescence — it actively drives the cell towards it.

Through our work, we found that the change in transcription is the root cause of senescence-like proteome remodeling.⁴ We also find clues for molecular players that may be involved in this size-dependent regulation of transcription, and show that scaling transcription may be achieved by scaling of productive transcription time. Finally, we also find that organelles in large cells, specifically lysosomes, can be made vulnerable to perturbation, which may be useful for combination therapies targeting cancer cells. See Interpretations.

The approach

Dissecting the gene expression pathway across cell size

Using genetically engineered cells of different sizes, we asked: how does each step of gene expression change with cell size? Transcription (MS2 live imaging), mRNA stability (SLAMseq), and protein turnover (pulse-SILAC-TMT) were each measured independently. See Tools. Our results suggest that size-dependent transcription is the primary source of proteome remodeling. See Results.