Nuclear Morphological Remodeling in Human Granulocytes Is Linked to Prenylation Independently from Cytoskeleton.

Sebastian Martewicz,Camilla Luni,Xi Zhu,Meihua Cui,Damiano Buratto,Nicola Elvassore,Siqi Qu,Eleonora Grespan,Guang Yang,Manli Hu

doi:10.3390/cells9112509

Abstract

Nuclear shape modulates cell behavior and function, while aberrant nuclear morphologies correlate with pathological phenotype severity. Nevertheless, functions of specific nuclear morphological features and underlying molecular mechanisms remain poorly understood. Here, we investigate a nucleus-intrinsic mechanism driving nuclear lobulation and segmentation concurrent with granulocyte specification, independently from extracellular forces and cytosolic cytoskeleton contributions. Transcriptomic regulation of cholesterol biosynthesis is equally concurrent with nuclear remodeling. Its putative role as a regulatory element is supported by morphological aberrations observed upon pharmacological impairment of several enzymatic steps of the pathway, most prominently the sterol ∆14-reductase activity of laminB-receptor and protein prenylation. Thus, we support the hypothesis of a nuclear-intrinsic mechanism for nuclear shape control with the putative involvement of the recently discovered GGTase III complex. Such process could be independent from or complementary to the better studied cytoskeleton-based nuclear remodeling essential for cell migration in both physiological and pathological contexts such as immune system function and cancer metastasis.

Highlights

In recent years, nuclear shape is transcending the definition of mere morphological cell feature and is increasingly recognized for its structural purposes and its role in regulating cellular functions
The cytoskeleton is broadly regarded as the main regulator of nuclear morphology, especially as a consequence of studies in migratory cells, where dynamic nuclear remodeling relies on specialized cytoskeletal structures exerting forces to push, pull, and squeeze while pivoting on cell-substrate anchoring points [1,13,14,15,16]
We first sought to define the role of the three main cytoskeletal components (actin microfilaments (MFs), microtubules (MTs), and intermediate filaments (IFs)) in maintaining the lobular and segmented nuclear structure in induced HL60 cells

Summary

Introduction

Nuclear shape is transcending the definition of mere morphological cell feature and is increasingly recognized for its structural purposes and its role in regulating cellular functions. The cytoskeleton is broadly regarded as the main regulator of nuclear morphology, especially as a consequence of studies in migratory cells, where dynamic nuclear remodeling relies on specialized cytoskeletal structures exerting forces to push, pull, and squeeze while pivoting on cell-substrate anchoring points [1,13,14,15,16]. In such systems, nuclear morphology is directly linked to extracellular features. While cytoplasmic cytoskeletal elements coexist with these structures [17], the causality between the two is still debated [9] and far only observed under special or pathological conditions [18,19]

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