Lis1 regulates Phagocytosis by co-localising with actin in the Phagocytic cup
Preprint posted on 8 November 2019 https://www.biorxiv.org/content/10.1101/835769v1.full
Under certain circumstances the life of a cell requires the ingestion of large particles from the environment in a process called phagocytosis. Upon encountering a foreign object, the cell membrane of the engulfing cell begins to protrude and wrap around the particle until it is fully enveloped and can pinch off into the cytosol as a discreet structure called a phagophore. The phagophore then fuses with lysosomes so the ingested contents can be degraded. The process of membrane protrusion during phagocytosis requires actin reorganisation and polymerisation to deform and support the enveloping membrane. Indeed, numerous actin nucleators, severing, bundling and cross-linking proteins have been localised to the early phagophore membrane1.
In this study the authors investigate the role of an unconventional actin regulator Lis1 in phagocytosis. Lis1 is best known as a regulator of the minus end-directed microtubule motor complex dynein with which it binds to improve the persistence of motor generated force. However, recent studies have suggested that Lis1 is also able to regulate the actin cytoskeleton at focal adhesions and during migration hence its interest here.
To investigate whether Lis1 plays a role in phagocytosis, RAW 264.7 macrophages in which Lis1 was either depleted or overexpressed were fed 2.5um silica beads for 5 minutes and the number of internalised beads counted. Surprisingly in both situations phagocytosis was found to be impaired, leading the authors to conclude that optimum levels of Lis1 are required for efficient ingestion.
In the amoeba Dictyostelium and in neurons, impairment of Lis1 has been proposed to affect actin dynamics by reducing F actin content. The authors therefore looked to see whether changing the balance of G and F actin affects phagocytosis in a similar way to altered levels of Lis1. Treatment of Dictyostelium with either LatrunculinA or Jasplakinolide to depolymerise or stabilise actin filaments respectively both reduced the efficiency of phagocytosis. This implies a balance of F and G actin is required. Interestingly, overexpression of Lis1, which is predicted to increase F actin, was partially rescued by treatment with LatrunculinA, which reduces F actin, supporting this idea of Lis1 activity.
The authors also pinpointed Lis1 activity to the early stages of phagocytosis, since phagocytic membrane progression around beads in the first five minutes of ingestion was reduced in Dictyostelium over expressing Lis1. Furthermore, Lis1 levels were found to be enriched on early phagosomes relative to late phagosomes. Interestingly dynein levels remained constant.
In conclusion, the favoured model presented by the authors to summarise this data is that optimal amounts of Lis1 help to recruit optimal numbers of actin nucleators to support F actin levels and progression of the phagocytic cup. Too much Lis1 and an excess of nucleators renders the cup less dynamic and too few hinders membrane protrusion.
This is not the first time that dynein subunits and regulators have been shown to have dynein independent functions. For example, the dynein light chain Tctex1 is also capable of regulating actin remodelling2. The light chain LC8 also appears to have dynein-independent roles in redox sensing and transcriptional control3. I chose this preprint because it serves as an exciting reminder of the versatility of protein function – just when you think you know a protein there is always more to discover. The increasing number of links between microtubule and actin regulators being discovered is a source of fascination for me and I believe the complexity of crosstalk between different cytoskeletal elements, especially at the cortex, is still a relatively poorly explored field with lots to uncover before the system is fully understood.
Questions for authors
How is Lis1 is recruited to the phagophore membrane? Does it bind actin directly or is it part of a raft of proteins at this site and what signals could drive recruitment? Perhaps this could be determined from pull downs and mass spectrometry from isolated phagosomes.
Is it known what microtubules are doing at the phagocytic cup? Do they play a role and does microtubule depolymerisation affect phagocytosis? If not, this would support the model that Lis1 is acting independently of dynein, or perhaps Lis1 could be playing multiple roles.
Does jasplakinolide treatment rescue Lis1 depletion just as latrunculinA does for overexpression? Perhaps this could be tested in macrophages given the difficulties of depletion in Dictyostelium.
- Phagocytosis and the actin cytoskeleton. May, R.C. and Machesky L. M. Journal of Cell Science. 2001. 114(6):1061-77
- The Dynein Light Chain Tctex-1 Has a Dynein-Independent Role in Actin Remodeling during Neurite Outgrowth. Chuang, J. Yeh, T. Bollati, F. Conde, C. Canavosio, F. Caceres, A. Sung, C. Developmental Cell. 9(1):75-86
- Dynein-Independent Functions of DYNLL1/LC8: Redox State Sensing and Transcriptional Control. King. M. Science Signaling. 2008. 1(47):51
Posted on: 19 November 2019Read preprint
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